Nicotinyl riboside compounds and their uses

ABSTRACT

The disclosure provides nicotinamide riboside (NR), the reduced form of NR (NRH), nicotinic acid riboside (NAR), the reduced form of NAR (NARH), derivatives thereof, compositions thereof and uses thereof. The NR and NAR derivatives have improved stability and bioavailability compared to NR and NAR. NR, NRH, NAR, NARH, and derivatives thereof can increase intracellular NAD +  levels, and can enhance mitochondrial and cellular function and cell viability. Therefore, NR, NRH, NAR, NARH, and derivatives thereof, whether alone or in combination with one or more additional therapeutic agents (e.g., a PARP inhibitor), are useful for treating mitochondrial diseases, mitochondria-related diseases and conditions, and other disorders and conditions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a 35 USC § 371 of International Application serialNo. PCT/US2019/066064, filed Dec. 12, 2019, which claimed the benefit ofU.S. Provisional App. No. 62/780,559 filed on Dec. 17, 2018, whosedisclosures are incorporated by reference in their entirety.

INCORPORATION BY REFERENCE OF SEQUENCE LISTING

This application incorporates by reference the sequence listing in theASCII text file entitled “34993-002WO_SL”, created on Mar. 4, 2020, filesize 929 bytes. This sequence listing has been filed at the U.S. Patentand Trademark Office with the other documents for this application.

FIELD OF THE DISCLOSURE

The disclosure relates to nicotinamide riboside (NR), the reduced formof NR (NRH), nicotinic acid riboside (NAR), the reduced form of NAR(NARH), derivatives thereof, compositions thereof and uses thereof toincrease NAD⁺ levels, to enhance mitochondrial and cellular function andcell viability, and to treat or prevent mitochondrial diseases,mitochondria-related diseases and other diseases.

BACKGROUND OF THE DISCLOSURE

Nicotinamide adenine dinucleotide (NAD) is a coenzyme that is criticalfor cellular function. It serves two major functions. First, NAD servesas a carrier for redox functions. These are chemical reactions involvingthe transfer of electrons and form the basis for energy production inevery cell [Croteau et al. (2017); Fang et al. (2017); Chini et al.(2016); and Yang et al. (2016)]. The oxidized form of NAD is abbreviatedNAD⁺, and the reduced form of NAD is abbreviated NADH. NAD⁺ is anoxidizing agent that accepts electrons from other molecules to formNADH, which in turn is a reducing agent that donates electrons to othermolecules. Such electron-transfer reactions are the main function ofNAD.

Second, NAD is an essential cofactor in several non-redox reactions byproviding ADP-ribose to catalyze the enzymatic function of two keyprotein families—the sirtuins (SIRTs) and the poly(ADP-ribose)polymerases (PARPs). SIRTs are deacetylases involved in the maintenanceof nuclear, mitochondrial and cytoplasmic or metabolic homeostasis (Ref.1-3). PARPs are involved in DNA repair and play a broad role in themaintenance of chromatin structure and function [Croteau et al. (2017);Fang et al. (2017); Chini et al. (2016); and Yang et al. (2016)].

When NAD⁺ levels are depleted, cellular functioning is impaired due toboth reduced level of energy production and disruption of cellularhomeostasis. Reduction in NAD⁺ levels is observed in physiologicalstates such as in aging, and across a wide range of pathological statesranging from acute injury to chronic metabolic and inflammatoryconditions [Bonkowski et al. (2016); Frederick et al. (2016); Zang etal. (2016); and Imai et al. (2014)]. In particular, given the centralrole of the mitochondria in energy production, organs with highernumbers of mitochondria such as the liver, heart, skeletal muscle, brainand kidneys are most susceptible to NAD⁺ depletion and thus are mostamenable to therapies that can enhance NAD⁺ levels [Bonkowski et al.(2016); Frederick et al. (2016); Zang et al. (2016); and Imai et al.(2014)]. In addition, efficient mitochondrial activity is critical forimmune cell function, and mitochondrial dysfunction is associated withpoor immune surveillance (impaired antigen recognition and immuneexhaustion) and immune cell senescence [Bonkowski et al. (2016);Frederick et al. (2016); Zang et al. (2016); and Imai et al. (2014)].

There are several approaches to enhancing NAD⁺ levels based on thedifferent ways NAD is synthesized in the body. In each such instance,the starting point is usually a compound obtained from the diet. Suchcompounds include dietary tryptophan, and derivatives of vitamin B₃ thatinclude nicotinic acid (NA), nicotinamide (NAM), nicotinamide riboside(NR) and nicotinamide mononucleotide (NMN). While NAD can also beobtained in the diet, it is rapidly broken down into NAM or NR byextracellular hydrolases such as CD38 and CD73 [Camacho-Pereira et al.(2016)].

Nicotinamide, nicotinic acid and nicotinamide riboside are naturalcompounds that are currently available as nutritional supplements. NMNis a nucleotide derivative of NAM that is considered to be a biochemicalprecursor of NAD⁺. There is in vitro data showing that NR and NMN inparticular can elevate NAD⁺ levels. Further, in animal models NR and NMNelevate NAD⁺ levels and improve organ function [Fang et al. (2016);Mills et al. (2016); de Picciotto et al. (2016); and Zang et al.(2016)], disease pathology and longevity [Fang et al. (2016); Mills etal. (2016); de Picciotto et al. (2016); and Zang et al. (2016)].

While NR and NMN are useful as precursors of NAD⁺ and can potentiallyelevate levels of NAD⁺ and thus promote cellular health andmitochondrial function, the bioavailability of these molecules is notoptimal for their use as pharmacological and nutritional agents[Ratajczak et al. (2016) and Trammell et al. (2016)]. The reasons fortheir poor bioavailability include pH-dependent stability, degradationdue to hydrolysis, and the need for enzymatic conversion within the cellto NAD for biological effects.

SUMMARY OF THE DISCLOSURE

The disclosure relates to nicotinamide riboside (NR), the reduced formof NR (NRH), nicotinic acid riboside (NAR), the reduced form of NAR(NARH), derivatives thereof, compositions thereof and uses thereof,including to increase NAD⁺ levels, to enhance mitochondrial and cellularfunction and cell viability, to provide cytoprotection, and to treat orprevent mitochondrial diseases, mitochondria-related disorders and otherdisorders.

The disclosure provides compounds of Formulas I and II.

wherein R¹, R² and R³ are defined elsewhere herein.

The disclosure further provides compounds of Formulas III and IV:

wherein R⁴, R⁵ and R⁶ are defined elsewhere herein.

The compounds of Formulas I, II, III and IV can increase NAD⁺ levels inthe mitochondria, the cytoplasm or/and the nucleus of cells (e.g., totalcellular NAD⁺ level) and can enhance mitochondrial and cellular functionand cell viability, and have suitable bioavailability and stability inintracellular and extracellular environments. Therefore, the compoundsare useful for treating mitochondrial diseases, mitochondria-relateddiseases and conditions, diseases and conditions characterized by acuteNAD⁺ depletion due to DNA damage, and other disorders and conditions.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates an exemplary process for making compounds of FormulasI and II, which can be adapted to make compounds of Formulas III and IV.

FIG. 2 shows a process for synthesizing MP-05 and MP-06.

FIG. 3 shows a process for synthesizing MP-07 and MP-08.

FIG. 4 shows a process for synthesizing MP-09 and MP-10.

FIG. 5 shows a process for synthesizing MP-14 and MP-16.

FIG. 6 shows a process for synthesizing MP-12 and MP-15.

FIG. 7 shows a process for synthesizing MP-17, MP-20, MP-23 and MP-24.

FIG. 8 shows a process for synthesizing MP-18, MP-19, MP-21 and MP-22.

FIG. 9 shows a process for synthesizing MP-17 and MP-20.

FIG. 10 shows a process for synthesizing MP-41.

FIG. 11 shows a process for synthesizing MP-42.

FIG. 12 shows % recovery of NAD⁺ level depleted by the DNA-alkylatingmutagen methynitronitrosoguanidine (MNNG) in Jurkat cells with varyingconcentrations of MP-17.

FIG. 13 shows % reduction of MNNG-induced cytotoxicity in Jurkat cellswith varying concentrations of MP-17.

FIG. 14 shows % recovery of NAD⁺ level depleted by MNNG in Jurkat cellswith varying concentrations of MP-41.

FIG. 15 shows % reduction of MNNG-induced cytotoxicity in Jurkat cellswith varying concentrations of MP-41.

FIG. 16 shows synergistic repletion of NAD⁺ level in MNNG-treated Jurkatcells by a combination of nicotinamide riboside (“MP02” in FIG. 16 ) anda very low concentration (5 nM) of the PARP inhibitor olaparib.

FIG. 17 shows synergistic cytoprotection (reduction of cytotoxicity) inMNNG-treated Jurkat cells by a combination of nicotinamide riboside(“MP02” in FIG. 17 ) and a very low concentration (5 nM) of olaparib.

GENERAL STATEMENTS

While various embodiments of the present disclosure are describedherein, it will be obvious to those skilled in the art that suchembodiments are provided by way of example only. Numerous modificationsand changes to, and variations and substitutions of, the embodimentsdescribed herein will be apparent to those skilled in the art withoutdeparting from the disclosure. It is understood that variousalternatives to the embodiments described herein can be employed inpracticing the disclosure. It is also understood that every embodimentof the disclosure can optionally be combined with any one or more of theother embodiments described herein which are consistent with thatembodiment.

Where elements are presented in list format (e.g., in a Markush group),it is understood that each possible subgroup of the elements is alsodisclosed, and any one or more elements can be removed from the list orgroup.

It is also understood that, unless clearly indicated to the contrary, inany method described or claimed herein that includes more than one actor step, the order of the acts or steps of the method is not necessarilylimited to the order in which the acts or steps of the method arerecited, but the disclosure encompasses embodiments in which the orderis so limited.

It is further understood that, in general, where an embodiment in thedescription or the claims is referred to as comprising one or morefeatures, the disclosure also encompasses embodiments that consist of,or consist essentially of, such feature(s).

It is also understood that any embodiment of the disclosure, e.g., anyembodiment or compound found within the prior art, can be explicitlyexcluded from the claims, regardless of whether or not the specificexclusion is recited in the specification.

It is further understood that the present disclosure encompasses salts,solvates, hydrates, clathrates and polymorphs of all of the compoundsdisclosed herein. The specific recitation of “salts”, “solvates”,“hydrates”, “clathrates” or “polymorphs” with respect to a compound or agroup of compounds in certain instances of the disclosure shall not beinterpreted as an intended omission of any of these forms in otherinstances of the disclosure where the compound or the group of compoundsis mentioned without recitation of any of these forms, unless statedotherwise or the context clearly indicates otherwise.

All patent literature and all non-patent literature cited herein areincorporated herein by reference in their entirety to the same extent asif each patent literature or non-patent literature were specifically andindividually indicated to be incorporated herein by reference in itsentirety.

Definitions

Unless defined otherwise or clearly indicated otherwise by their useherein, all technical and scientific terms used herein have the samemeaning as commonly understood by those of ordinary skill in the art towhich this application belongs.

As used in the specification and the appended claims, the indefinitearticles “a” and “an” and the definite article “the” can include pluralreferents as well as singular referents unless specifically statedotherwise or the context clearly indicates otherwise.

The term “exemplary” as used herein means “serving as an example,instance or illustration”. Any embodiment or feature characterizedherein as “exemplary” is not necessarily to be construed as preferred oradvantageous over other embodiments or features.

In some embodiments, the term “about” or “approximately” means within±10% or 5% of the given value. Whenever the term “about” or“approximately” precedes the first numerical value in a series of two ormore numerical values or in a series of two or more ranges of numericalvalues, the term “about” or “approximately” applies to each one of thenumerical values in that series of numerical values or in that series ofranges of numerical values.

Whenever the term “at least” or “greater than” precedes the firstnumerical value in a series of two or more numerical values, the term“at least” or “greater than” applies to each one of the numerical valuesin that series of numerical values.

Whenever the term “no more than” or “less than” precedes the firstnumerical value in a series of two or more numerical values, the term“no more than” or “less than” applies to each one of the numericalvalues in that series of numerical values.

The term “agent” denotes a chemical compound, a mixture of chemicalcompounds, a biological macromolecule (such as a nucleic acid, apolypeptide or a portion thereof, or an antibody or a fragment thereof),a mixture of biological macromolecules, or an extract of a biologicalmaterial such as an animal (particularly a mammalian) cell or tissue, aplant, a bacterium or a fungus. The term “polypeptides” includespeptides (e.g., polypeptides containing no more than about 50 amino acidresidues) and proteins (which are larger polypeptides).

A “modulator” of, e.g., a receptor or enzyme can be an activator orinhibitor of that receptor or enzyme, and can increase or reduce theactivity or/and the level of that receptor or enzyme. For example, a“sirtuin-modulating compound” can be an activator or inhibitor of asirtuin, and can increase or reduce the activity or/and the level of asirtuin.

The term “therapeutic agent” refers to any biologically, physiologicallyor pharmacologically active substance that acts locally or systemicallyin a subject and is administered to a subject for purposes of diagnosis,treatment, mitigation, cure or prevention of a medical condition orenhancement of a desired physical or mental development or condition.

The term “therapeutically effective amount” refers to an amount of anagent that, when administered to a subject, is sufficient to prevent,reduce the risk of developing, delay the onset of, slow the progressionof or cause regression of the medical condition being treated, or toalleviate to some extent the medical condition or one or more symptomsor complications of that condition, at least in some fraction of thesubjects taking that agent. The term “therapeutically effective amount”also refers to an amount of an agent that is sufficient to elicit thebiological or medical response of a cell, tissue, organ, system, animalor human which is sought by a researcher, veterinarian, medical doctoror clinician.

The terms “treat”, “treating” and “treatment” include alleviating,ameliorating, inhibiting the progress of, reversing or abrogating amedical condition or one or more symptoms or complications associatedwith the condition, and alleviating, ameliorating or eradicating one ormore causes of the condition. Reference to “treatment” of a medicalcondition includes prevention of the condition. The terms “prevent”,“preventing” and “prevention” include precluding, reducing the risk ofdeveloping and delaying the onset of a medical condition or one or moresymptoms or complications associated with the condition.

The term “medical conditions” (or “conditions” for short) includesdiseases and disorders. The terms “diseases” and “disorders” are usedinterchangeably herein.

“Diabetes mellitus” (or “diabetes” for short) is a metabolic disordercharacterized by high blood sugar level over a prolonged period, and caninclude complications such as ketoacidosis. Diabetes is characterized bychronic, general metabolic abnormalities resulting from prolonged highblood sugar level or/and a decrease in glucose tolerance. The main typesof diabetes include type 1 diabetes (T1D), type 2 diabetes (T2D) andgestational diabetes.

“Mitochondrial diseases” are disorders caused by dysfunctionalmitochondria, and occur when the mitochondria of the cell, e.g., fail toproduce enough energy for cell or organ function, or produce excessiveamounts of reactive oxygen species (ROS) that cause oxidative damage tothe cell or components thereof or lead to other pathological effects. Amitochondrial disease can be due to, e.g., a congenital geneticdeficiency or defect (e.g., a mutation or deletion in mitochondrial DNAresulting in defective mitochondria), or an acquired deficiency ordefect. A mitochondrial disease can be caused by, e.g., oxidative damageduring aging, excessive mitochondrial calcium level, excessive exposureof affected cells to nitric oxide, ischemia, hypoxia,microtubule-associated deficit in axonal transport of mitochondria, orexcessive expression of mitochondrial uncoupling proteins. Congenitalmitochondrial diseases result from, e.g., hereditary mutations,deletions or other defects in mitochondrial DNA or in nuclear genesencoding proteins (e.g., those regulating mitochondrial DNA function orintegrity). Acquired mitochondrial defects can be caused by, e.g.,damage to mitochondrial DNA due to oxidative processes or aging,mitochondrial dysfunction, inhibition of respiratory chain complexes,mitochondrial respiration deficiencies and defects, oxygen deficiency,impaired nuclear-mitochondrial interactions, and excessive expression ofmitochondrial uncoupling proteins in response to, e.g., lipids,oxidative damage or inflammation.

The term “subject” refers to an animal, including but not limited to amammal, such as a primate (e.g., a human, a chimpanzee or a monkey), arodent (e.g., a rat, a mouse, a guinea pig, a gerbil or a hamster), alagomorph (e.g., a rabbit), a bovine (e.g., a cattle), a suid (e.g., apig), a caprine (e.g., a sheep), an equine (e.g., a horse), a canine(e.g., a dog) or a feline (e.g., a cat). The terms “subject” and“patient” are used interchangeably herein in reference, e.g., to amammalian subject, such as a human subject.

The term “bioavailable”, when referring to an agent, refers to theextent to which the agent is taken up by a cell, tissue or organ, orotherwise physiologically available to the subject after administration.

The term “parenteral” refers to a route of administration other thanthrough the alimentary canal, such as by injection, infusion orinhalation. Parenteral administration includes without limitationsubcuticular, intradermal, subcutaneous, intravascular, intravenous,intra-arterial, intramuscular, intracardiac, intraperitoneal,intracavitary, intra-articular, intracapsular, subcapsular,intra-orbital, transtracheal, intrasternal, intrathecal, intramedullary,intraspinal, subarachnoid and topical administrations. Topicaladministration includes without limitation dermal/epicutaneous,transdermal, mucosal, transmucosal, intranasal (e.g., by nasal spray ordrop), ocular (e.g., by eye drop), pulmonary (e.g., by oral or nasalinhalation), buccal, sublingual, rectal (e.g., by suppository), andvaginal (e.g., by suppository).

The term “pharmaceutically acceptable” refers to a substance (e.g., anactive ingredient or an excipient) that is suitable for use in contactwith the tissues and organs of a subject without excessive irritation,allergic response, immunogenicity and toxicity, is commensurate with areasonable benefit/risk ratio, and is effective for its intended use. A“pharmaceutically acceptable” excipient or carrier of a pharmaceuticalcomposition is also compatible with the other ingredients of thecomposition.

The term “nicotinyl (or nicotinoyl or nicotinic) riboside compounds” asused herein includes nicotinamide riboside (NR), the reduced form of NR(NRH), nicotinic acid riboside (NAR), the reduced form of NAR (NARH),and derivatives thereof. As used herein, the term “nicotinamide riboside(NR) derivatives” includes derivatives of both the oxidized form and thereduced form of NR, and the term “nicotinic acid riboside (NAR)derivatives” includes derivatives of both the oxidized form and thereduced form of NAR.

The disclosure encompasses salts, solvates, hydrates, clathrates andpolymorphs of the compounds described herein. A “solvate” of a compoundincludes a stoichiometric or non-stoichiometric amount of a solvent(e.g., water, acetone or an alcohol [e.g., ethanol]) boundnon-covalently to the compound. A “hydrate” of a compound includes astoichiometric or non-stoichiometric amount of water boundnon-covalently to the compound. A “clathrate” of a compound containsmolecules of a substance (e.g., a solvent) enclosed in the crystalstructure of the compound. A “polymorph” of a compound is a crystallineform of the compound.

The term “alkyl” refers to a linear (straight chain) or branched,saturated monovalent hydrocarbon radical. The term “lower alkyl” refersto a linear C₁-C₆ or branched C₃-C₆ alkyl group. Lower alkyl groupsinclude without limitation methyl, ethyl, propyl (including n-propyl andisopropyl), butyl (including all isomeric forms, such as n-butyl,isobutyl, sec-butyl and tert-butyl), pentyl (including all isomericforms, such as n-pentyl), and hexyl (including all isomeric forms, suchas n-hexyl).

The term “cycloalkyl” refers to a cyclic saturated monovalenthydrocarbon radical. C₃-C₆ cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl.

Examples of 3- to 6-membered, nitrogen-containing heterocyclic ringsinclude without limitation aziridinyl, azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl and morpholinyl.

DETAILED DESCRIPTION OF THE DISCLOSURE

The disclosure provides nicotinamide riboside (NR), the reduced form ofNR (NRH), nicotinic acid riboside (NAR), the reduced form of NAR (NARH),derivatives thereof, pharmaceutical compositions thereof and usesthereof. The NR and NAR derivatives described herein can act asprecursors or prodrugs of NR/NRH and NAR/NARH and thereby serve assources of NR/NRH and NAR/NARH with improved stability andbioavailability.

Both the oxidized form and the reduced form of both NR and NAR can beconverted within the body to NMN and then to NAD⁺. Alternatively,without intending to be bound by theory, NRH and NARH may be convertedto a reduced form of NMN and NAMN (NMNH and NAMNH), which may then beconverted to NADH, which functions as a reducing agent in redoxreactions and becomes oxidized to NAD⁺ in the process. By increasingNAD⁺ levels, the NR and NAR derivatives can enhance mitochondrial andcellular function and provide cytoprotection, and thus are useful fortreating mitochondrial diseases, mitochondria-related diseases andconditions, diseases and conditions associated with acute NAD⁺ depletioninduced by DNA damage, and other disorders.

NR and NAR Derivatives

In some embodiments, NR and NAR derivatives have Formulas I and II.

wherein:

-   -   R¹ is hydrogen,

-   -    wherein:        -   R^(a) is hydrogen, a counterion, linear or branched C₁-C₆            alkyl, C₃-C₆ cycloalkyl, phenyl, 1-naphthyl or 2-naphthyl,            wherein the phenyl is optionally substituted with F, Cl,            —NO₂, linear or branched C₁-C₄ alkyl, —CF₃ or —O-(linear or            branched C₁-C₄ alkyl);        -   R^(b) and R^(c) at each occurrence independently are            hydrogen, linear or branched C₁-C₅ alkyl, —CH₂-phenyl,            —CH₂-3-indole or —CH₂-5-imidazole, wherein the alkyl is            optionally substituted with —OH, —OR^(j), —SH, —SR^(j),            —NH₂, —NHR^(j), —N(R^(j))₂, —NHC(═O)R^(j), —NHC(═NH)NH₂,            —C(═O)NH₂, —CO₂H or —C(═O)OR^(j), and the phenyl is            optionally substituted with —OH or —OR^(j), wherein R^(j) at            each occurrence independently is linear or branched C₁-C₄            alkyl;        -   R^(d) at each occurrence independently is hydrogen, methyl            or linear or branched C₂-C₄ alkyl;        -   R^(e) and R^(f) at each occurrence independently are            hydrogen, a counterion, linear or branched C₁-C₈ alkyl,            C₃-C₆ cycloalkyl, —CH₂—(C₃-C₆ cycloalkyl), phenyl or            —CH₂-phenyl, wherein the phenyl is optionally substituted            with F, Cl, —NO₂, linear or branched C₁-C₄ alkyl, —CF₃ or            —O-(linear or branched C₁-C₄ alkyl);        -   R^(k) is hydrogen, linear or branched C₁-C₆ alkyl,            —CH₂-phenyl, —CH₂-3-indole or —CH₂-5-imidazole, wherein the            alkyl is optionally substituted with —OH, —OR^(j), —SH,            —SR^(j), —NH₂, —NHR^(j), —N(R^(j))₂, —NHC(═O)R^(j),            —NHC(═NH)NH₂, —C(═O)NH₂, —CO₂H or —C(═O)OR^(j), and the            phenyl is optionally substituted with —OH or —OR^(j),            wherein R^(j) at each occurrence independently is linear or            branched C₁-C₄ alkyl;        -   R^(m) is hydrogen, a counterion, linear or branched C₁-C₆            alkyl, C₃-C₆ cycloalkyl, phenyl, —CH₂-phenyl or

-   -   -    wherein the phenyl is optionally substituted with F, Cl,            —NO₂, linear or branched C₁-C₄ alkyl, —CF₃ or —O-(linear or            branched C₁-C₄ alkyl); and        -   X is cis or trans —HC═CH— or —(CH₂)_(n)— optionally            substituted with —OH, —OR^(j) or —OC(═O)R^(j), wherein R^(j)            is linear or branched C₁-C₄ alkyl and n is 1, 2, 3, 4, 5 or            6;

    -   R² at each occurrence independently is hydrogen,

-   -    wherein:        -   R⁹ is hydrogen, linear or branched C₁-C₅ alkyl, —CH₂-phenyl,            —CH₂-3-indole or —CH₂-5-imidazole, wherein the alkyl is            optionally substituted with —OH, —OR^(j), —SH, —SR^(j),            —NH₂, —NHR^(j), —N(R^(j))₂, —NHC(═O)R^(j), —NHC(═NH)NH₂,            —C(═O)NH₂, —CO₂H or —C(═O)OR^(j), and the phenyl is            optionally substituted with —OH or —OR^(j), wherein R^(j) at            each occurrence independently is linear or branched C₁-C₄            alkyl;        -   R^(h) is hydrogen, methyl or —NH₂;        -   or R^(g) and R^(h) together with the carbon atom to which            they are connected form a C₃-C₆ cycloalkyl or phenyl ring,            wherein the phenyl ring is optionally substituted with F,            Cl, —NO₂, linear or branched C₁-C₄ alkyl, —CF₃ or —O-(linear            or branched C₁-C₄ alkyl); and        -   R^(m) and X are as defined above; and    -   R³ is —NH₂, —NHR^(n), —N(R^(n))₂, —OH, —OR^(o) or

-   -    wherein:        -   R^(n) at each occurrence independently is linear or branched            C₁-C₆ alkyl or allyl, wherein the alkyl is optionally            substituted with —OH or —O-(linear or branched C₁-C₃ alkyl),            or both occurrences of R^(n) and the nitrogen atom to which            they are connected form a 3- to 6-membered heterocyclic            ring; and        -   R^(o) is a counterion, linear or branched C₁-C₆ alkyl, C₃-C₆            cycloalkyl, phenyl or —CH₂-phenyl, wherein the phenyl is            optionally substituted with F, Cl, —NO₂, linear or branched            C₁-C₄ alkyl, —CF₃ or —O-(linear or branched C₁-C₄ alkyl);    -   or pharmaceutically acceptable salts, solvates, hydrates,        clathrates, polymorphs or stereoisomers thereof;    -   with the proviso that:        -   1) R¹ and both occurrences of R² all are not hydrogen except            when R³ is

-   -   -    and        -   2) the compounds of Formulas I and II are not:

or salts or stereoisomers thereof.

However, the compounds excluded from Formulas I and II above can beincluded within the scope of NR/NAR derivatives generally, or within thescope of Formulas I and II more specifically, in some embodiments ofpharmaceutical compositions and therapeutic or medical uses.

In some embodiments, when both occurrences of R² are acetyl:

1) R¹ is not hydrogen; or

2) R³ is not —NH₂ or —OH or a salt thereof; or

3) R¹ is not hydrogen and R³ is not —NH₂ or —OH or a salt thereof.

In certain embodiments, when R¹ is

1) both occurrences of R² are not hydrogen; or2) R³ is not —NH₂ or —OH or a salt thereof; or3) both occurrences of R² are not hydrogen and R³ is not —NH₂ or —OH ora salt thereof.

In some embodiments, when R¹ is

1) both occurrences of R² are not hydrogen; or2) R³ is not —NH₂ or —OH or a salt thereof; or3) both occurrences of R² are not hydrogen and R³ is not —NH₂ or —OH ora salt thereof.

In certain embodiments, when R¹ is

1) both occurrences of R² are not hydrogen; or2) R³ is not —NH₂ or —OH or a salt thereof; or3) both occurrences of R² are not hydrogen and R³ is not —NH₂ or —OH ora salt thereof.

In some embodiments, R¹ is

(phosphoramidate). In certain embodiments, R¹ is

and R^(e) is linear or branched C₁-C₆ alkyl. In certain embodiments,R^(e) is methyl, ethyl or isopropyl.

In further embodiments, R¹ is

(phosphorodiamidate/bisphosphoramidate). In certain embodiments, R¹ is

and both occurrences of R^(f) are linear or branched C₁-C₆ alkyl. Incertain embodiments, both occurrences of R^(f) are methyl, ethyl orisopropyl.

In other embodiments, R¹ is

In certain embodiments, R¹ is

and R^(k) is linear or branched C₁-C₆ alkyl. In certain embodiments,R^(k) is methyl, ethyl or isopropyl. An amino acid group can facilitatepenetration of an NR/NAR derivative through membrane barriers viapeptide transporters, such as peptide transporter 1 in the intestinalepithelium.

In additional embodiments, R¹, or/and R² at either occurrence or at bothoccurrences, is/are

In some embodiments, X is trans —HC═CH—, —CH₂CH₂— or —CH(OH)CH₂—, andR^(m) is hydrogen, a counterion, linear or branched C₁-C₆ alkyl (e.g.,methyl, ethyl or isopropyl) or

(an L-carnitine group). The —CH(OH)CH₂— portion can have theS-stereochemistry or a mixture (e.g., an approximately 1:1 ratio) ofS/R-stereochemistry. In certain embodiments, R¹, or/and R² at eitheroccurrence or at both occurrences, is/are selected from:

and salts thereof. A carnitine group can facilitate transport of anNR/NAR derivative into the mitochondria.

In some embodiments, R² at each occurrence independently, or at bothoccurrences, is hydrogen, —C(═O)-(linear or branched C₁-C₆ alkyl),

In certain embodiments, R² at each occurrence independently, or at bothoccurrences, is hydrogen, acetyl or propanoyl.

If a compound of Formula I or II comprises an amino acid group at R¹or/and at either occurrence or both occurrences of R², including anamino acid group in a phosphoramidate moiety at R¹ or two amino acidgroups in a phosphorodiamidate/bisphosphoramidate moiety at R¹, theamino acid group can independently be a natural amino acid or anunnatural amino acid. In some embodiments, an amino acid group isglycine, alanine, valine, leucine, isoleucine, methionine, proline,tryptophan, phenylalanine, tyrosine, serine, threonine, cysteine,asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine orhistidine, or a derivative thereof. In other embodiments, an amino acidgroup is an unnatural or non-proteinogenic amino acid, such asornithine, citrulline or homoarginine. In certain embodiments, an aminoacid group is glycine, alanine or valine. An amino acid group can be theL-isomer or the D-isomer, or can be a D/L (e.g., racemic) mixture. Incertain embodiments, an amino acid group is the L-isomer.

In some embodiments, R³ is —NH₂, —OH or a salt thereof, or

In certain embodiments, R³ is

an L-carnitine moiety. The carnitine moiety can exist as a zwitterion.

In some embodiments of compounds of Formulas I and II:

1) R¹ is

and both occurrences of R² are acetyl or propanoyl; or2) R¹ is

and R³ is —OH or a salt thereof; or3) R¹ is

both occurrences of R² are acetyl or propanoyl, and R³ is —OH or a saltthereof.In certain embodiments, R¹ is

and R^(e) is linear or branched C₁-C₆ alkyl. In certain embodiments,R^(e) is methyl, ethyl or isopropyl.

In further embodiments of compounds of Formulas I and II:

R¹ is

wherein R^(e) is linear or branched C₁-C₆ alkyl;

R² at both occurrences is —C(═O)-(linear or branched C₁-C₆ alkyl); and

R³ is —NH₂ or —OH or a salt thereof.

In certain embodiments, R^(e) of the R¹ moiety is methyl, ethyl orisopropyl, and both occurrences of R² are acetyl or propanoyl.

In other embodiments of compounds of Formulas I and II:

R¹ is

R² at each occurrence independently, or at both occurrences, ishydrogen, acetyl or propanoyl; and

R³ is —NH₂ or —OH or a salt thereof.

In some embodiments:

R^(b) and R^(c) at each occurrence independently are hydrogen or linearor branched C₁-C₅ alkyl, or each pair of R^(b) and R^(c) is hydrogen andlinear or branched C₁-C₅ alkyl;

R^(d) at both occurrences is hydrogen; and

R^(f) at both occurrences is linear or branched C₁-C₆ alkyl.

In certain embodiments, R¹ is

In further embodiments of compounds of Formulas I and II:

R¹ is

wherein both occurrences of R^(f) are linear or branched C₁-C₆ alkyl;

R² at each occurrence independently, or at both occurrences, is hydrogenor —C(═O)-(linear or branched C₁-C₆ alkyl); and

R³ is —NH₂ or —OH or a salt thereof.

In certain embodiments, both occurrences of R^(f) of the R¹ moiety aremethyl, ethyl or isopropyl, and R² at each occurrence independently, orat both occurrences, is hydrogen, acetyl or propanoyl.

In additional embodiments of compounds of Formulas I and II:

R¹ is

wherein R^(k) is linear or branched C₁-C₆ alkyl;

R² at each occurrence independently, or at both occurrences, is hydrogenor —C(═O)-(linear or branched C₁-C₆ alkyl); and

R³ is —NH₂ or —OH or a salt thereof.

In certain embodiments, R^(k) of the R¹ moiety is methyl, ethyl orisopropyl, and R² at each occurrence independently, or at bothoccurrences, is hydrogen, acetyl or propanoyl.

In other embodiments of compounds of Formulas I and II:

R¹ is

wherein:

-   -   X is cis or trans —HC═CH— or —(CH₂)_(n)— optionally substituted        with —OH, —OR^(j) or —OC(═O)R^(j), wherein R^(j) is linear or        branched C₁-C₄ alkyl and n is 1, 2, 3, 4, 5 or 6; and    -   R^(m) is hydrogen, a counterion, linear or branched C₁-C₆ alkyl        or

R² at each occurrence independently, or at both occurrences, is hydrogenor —C(═O)-(linear or branched C₁-C₆ alkyl); and

R³ is —NH₂ or —OH or a salt thereof.

In certain embodiments:

for the R¹ moiety, X is trans —HC═CH—, —CH₂CH₂— or —CH(OH)CH₂—, andR^(m) is hydrogen, a counterion, methyl, ethyl, isopropyl or

R² at each occurrence independently, or at both occurrences, ishydrogen, acetyl or propanoyl; and

R³ is —NH₂.

In some embodiments, the compounds of Formulas I and II are selectedfrom:

and pharmaceutically acceptable salts, solvates, hydrates, clathrates,polymorphs and stereoisomers thereof.

Other embodiments of the disclosure relate to NAR derivatives ofFormulas III and IV:

wherein:

R⁴ is hydrogen or —C(═O)R⁷, wherein R⁷ is linear or branched C₁-C₆alkyl, C₃-C₆ cycloalkyl, or phenyl optionally substituted with F, Cl,—NO₂, linear or branched C₁-C₄ alkyl, —CF₃ or —O-(linear or branchedC₁-C₄ alkyl);

R⁵ at each occurrence independently is hydrogen or —C(═O)R⁸, wherein R⁸has the same definition as R⁷; and

R⁶ is

and pharmaceutically acceptable salts, solvates, hydrate, clathrates,polymorphs and stereoisomers thereof.

In some embodiments of compounds of Formulas III and IV:

R⁴ is hydrogen or —C(═O)R⁷, wherein R⁷ is linear or branched C₁-C₆alkyl; and

R⁵ at each occurrence independently, or at both occurrences, is hydrogenor —C(═O)R⁸, wherein R⁸ is linear or branched C₁-C₆ alkyl.

In certain embodiments, R⁴ is hydrogen, acetyl or propanoyl, and R⁵ ateach occurrence independently, or at both occurrences, is hydrogen,acetyl or propanoyl. In preferred embodiments, the carnitine moiety ofR⁶ is the L-isomer

In certain embodiments, the compounds of Formulas III and IV areselected from:

and pharmaceutically acceptable salts, solvates, hydrates, clathrates,polymorphs and stereoisomers thereof.

The compounds of Formulas I, II, III and IV can comprise ahydrophobic/lipophilic group at R¹/R⁴, at either occurrence or bothoccurrences of R²/R⁵, or at R³, or any combination thereof. One or morehydrophobic groups can facilitate permeation of an NR/NAR derivativethrough membrane barriers, including the cell membrane. In certainembodiments, a hydrophobic group contains 6-20 or 8-20 carbon atoms. Insome embodiments, for the compounds of Formulas I and II:

-   -   R^(a) can be linear or branched C₁-C₂₀ alkyl;    -   R^(b) or R^(c) can be linear or branched C₁-C₂₀ alkyl for a        phosphoramidate moiety;    -   R^(b) or R^(c) at either occurrence or both occurrences can be        linear or branched C₁-C₂₀ alkyl for a        phosphorodiamidate/bisphosphoramidate moiety;    -   R^(e) can be linear or branched C₁-C₂₀ alkyl;    -   R^(f) at either occurrence or both occurrences can be linear or        branched C₁-C₂₀ alkyl;    -   R^(g) can be linear or branched C₁-C₂₀ alkyl;    -   R^(k) can be linear or branched C₁-C₂₀ alkyl;    -   R^(m) at any occurrence can be linear or branched C₁-C₂₀ alkyl;    -   R^(n) at any occurrence can be linear or branched C₁-C₂₀ alkyl;    -   R^(o) can be linear or branched C₁-C₂₀ alkyl; or    -   n for —(CH₂)_(n)— for X at any occurrence can be an integer from        1 to 20; or    -   any combination or all of the above.

In some embodiments, for the compounds of Formulas III and IV:

-   -   R⁷ can be linear or branched C₁-C₂₀ alkyl; or/and    -   R⁸ at either occurrence or both occurrences can be linear or        branched C₁-C₂₀ alkyl.

In some embodiments, the NR and NAR derivatives are the reducedform—i.e., have Formula II or IV.

The disclosure also encompasses isotopologues of the compounds ofFormulas I, II, III and IV. Isotopically enriched forms of the NR andNAR derivatives described herein include without limitation thoseenriched in the content of ²H (deuterium), ¹³C, ¹⁵N, ¹⁷O or ¹⁸O, or anycombination thereof, at one or more, or all, positions of thecorresponding atom(s).

Isomers of Compounds

The present disclosure encompasses all possible stereoisomers, includingboth enantiomers and all possible diastereomers in substantially pureform and mixtures of both enantiomers in any ratio (including a racemicmixture of enantiomers) and mixtures of two or more diastereomers in anyratio, of the compounds described herein, and not only the specificstereoisomers as indicated by drawn structure or nomenclature. Inpreferred embodiments, the disclosure relates to the specificstereoisomers indicated by drawn structure or nomenclature, includingthe beta-anomer of nicotinamide and nicotinic acid D-ribosidederivatives. The specific recitation of the phrase “or stereoisomersthereof” or the like with respect to a compound in certain instances ofthe disclosure shall not be interpreted as an intended omission of anyof the other possible stereoisomers of the compound in other instancesof the disclosure where the compound is mentioned without recitation ofthe phrase “or stereoisomers thereof” or the like, unless statedotherwise or the context clearly indicates otherwise.

In some embodiments, the NR and NAR derivatives are stereoisomericallypure. In some embodiments, at least about 90%, 95%, 98% or 99% of thecompounds of Formulas I, II, III and IV have the stereochemistryindicated by drawn structure or nomenclature, including thebeta-D-riboside configuration. In similar embodiments, the compounds ofFormulas I, II, III and IV have the beta-D-riboside configuration and anenantiomeric excess of at least about 80%, 90% or 95%.

In other embodiments, the compounds of Formulas I, II, III and IV aremixtures of enantiomers or mixtures of two or more diastereomers. Incertain embodiments, the compounds of Formulas I, II, III and IV areracemic mixtures. In other embodiments, the compounds of Formulas I, II,III and IV have the D-riboside configuration and a mixture ofbeta-/alpha-anomers. In certain embodiments, the compounds of FormulasI, II, III and IV have the D-riboside configuration and an approximately1:1 ratio of beta-alpha-anomers.

The description and all of the embodiments relating to isomers of the NRand NAR derivatives disclosed herein also apply to isomers of other NRand NAR derivatives (e.g., nicotinamide riboside triacetate [NRTA, i.e.,NR having an acetate group at each of the C-2, C-3 and C-5 positions ofriboside], the reduced form of NRTA [NRHTA], nicotinic acid ribosidetriacetate [NARTA], and the reduced form of NARTA [NARHTA]) and toisomers of NR, NRH, NAR and NARH.

Salt Forms of Compounds

The NR and NAR derivatives described herein can exist as salts, inparticular their oxidized form—i.e., NR and NAR derivatives of FormulasI and III. The disclosure encompasses all pharmaceutically acceptablesalts of NR and NAR derivatives. Examples of counteranions of salts ofNR and NAR derivatives, including those of Formulas I and III, includewithout limitation internal salt, fluoride, chloride, bromide, iodide,nitrate, sulfate, sulfite, phosphate, bicarbonate, carbonate,thiocyanate, formate, acetate, trifluoroacetate, glycolate, lactate,gluconate, ascorbate, benzoate, oxalate, malonate, succinate, citrate,methanesulfonate (mesylate), ethanesulfonate, propanesulfonate,benzenesulfonate (bezylate), p-toluenesulfonate (tosylate) andtrifluoromethanesulfonate (triflate). In certain embodiments, the NR andNAR derivatives, including those of Formulas I and III, are chloride,formate, acetate, trifluoroacetate or triflate salts.

If an NR or NAR derivative has an acidic group, such as a carboxylicacid group, it may form a salt with the acidic group. The countercationcan be, e.g., Li⁺, Na⁺, K⁺, Ca⁺², Mg⁺², ammonium, a protonated organicamine (e.g., diethanolamine) or a quaternary ammonium compound (e.g.,choline).

The description and all of the embodiments relating to salt forms of theNR and NAR derivatives disclosed herein also apply to salt forms ofother NR and NAR derivatives (e.g., NRTA, NRHTA, NARTA and NARHTA) andto salt forms of NR, NRH, NAR and NARH.

Pharmaceutical Compositions

The disclosure provides pharmaceutical compositions comprising one ormore NR/NAR derivatives described herein, or a pharmaceuticallyacceptable salt, solvate, hydrate, clathrate, polymorph or stereoisomerthereof, and one or more pharmaceutically acceptable excipients orcarriers. The compositions can optionally contain an additionaltherapeutic agent. In some embodiments, a pharmaceutical compositioncomprises a compound of Formula II or a compound of Formula IV. Infurther embodiments, a pharmaceutical composition comprises a compoundof Formula I and a compound of Formula II, or a compound of Formula IIIand a compound of Formula IV. A pharmaceutical composition generallycontains a therapeutically effective amount of the active ingredient,but can contain an appropriate fraction thereof. For purposes of thecontent of a pharmaceutical composition, the term “active ingredient”,“active agent”, “therapeutic agent” or “drug” encompasses a prodrug. Forbrevity, the term “pharmaceutical composition” encompasses a cosmeticcomposition.

A pharmaceutical composition contains an NR or NAR derivative insubstantially pure form. In some embodiments, the purity of the NR orNAR derivative is at least about 95%, 96%, 97%, 98% or 99%. In certainembodiments, the purity of the NR or NAR derivative is at least about98% or 99%. In addition, a pharmaceutical composition is substantiallyfree of contaminants or impurities. In some embodiments, the level ofcontaminants or impurities other than residual solvent in apharmaceutical composition is no more than about 5%, 4%, 3%, 2% or 1%relative to the combined weight of the intended active and inactiveingredients. In certain embodiments, the level of contaminants orimpurities other than residual solvent in a pharmaceutical compositionis no more than about 2% or 1% relative to the combined weight of theintended active and inactive ingredients.

Pharmaceutical compositions/formulations can be prepared in sterileform. For example, pharmaceutical compositions/formulations forparenteral administration by injection or infusion generally aresterile. Sterile pharmaceutical compositions/formulations are compoundedor manufactured according to pharmaceutical-grade sterilizationstandards known to those of skill in the art, such as those disclosed inor required by the United States Pharmacopeia Chapters 797, 1072 and1211, and 21 Code of Federal Regulations 211.

Pharmaceutically acceptable excipients and carriers includepharmaceutically acceptable substances, materials and vehicles.Non-limiting examples of types of excipients include liquid and solidfillers, diluents, binders, lubricants, glidants, surfactants,dispersing agents, disintegration agents, emulsifying agents, wettingagents, suspending agents, thickeners, solvents, isotonic agents,buffers, pH adjusters, absorption-delaying agents, stabilizers,antioxidants, preservatives, antimicrobial agents, antibacterial agents,antifungal agents, chelating agents, adjuvants, sweetening agents,flavoring agents, coloring agents, encapsulating materials and coatingmaterials. The use of such excipients in pharmaceutical formulations isknown in the art. For example, conventional vehicles and carriersinclude without limitation oils (e.g., vegetable oils such as olive oiland sesame oil), aqueous solvents {e.g., saline, buffered saline (e.g.,phosphate-buffered saline [PBS]) and isotonic solutions (e.g., Ringer'ssolution)}, and organic solvents (e.g., dimethyl sulfoxide [DMSO] andalcohols [e.g., ethanol, glycerol and propylene glycol]). Except insofaras any conventional excipient or carrier is incompatible with the activeingredient, the disclosure encompasses the use of conventionalexcipients and carriers in formulations containing one or more NR/NARderivatives. See, e.g., Remington: The Science and Practice of Pharmacy,21st Ed., Lippincott Williams & Wilkins (Philadelphia, Pa.) (2005);Handbook of Pharmaceutical Excipients, 5th Ed., Rowe et al., Eds., ThePharmaceutical Press and the American Pharmaceutical Association (2005);Handbook of Pharmaceutical Additives, 3rd Ed., Ash and Ash, Eds., GowerPublishing Co. (2007); and Pharmaceutical Pre-formulation andFormulation, Gibson, Ed., CRC Press (Boca Raton, Fla.) (2004).

Appropriate formulation can depend on various factors, such as the routeof administration chosen. Potential routes of administration ofpharmaceutical compositions containing one or more NR/NAR derivativesinclude without limitation oral, parenteral (including intradermal,subcutaneous, intramuscular, intravascular, intravenous, intra-arterial,intraperitoneal, intracavitary, intramedullary, intrathecal andtopical), and topical (including dermal/epicutaneous, transdermal,mucosal, transmucosal, intranasal [e.g., by nasal spray or drop], ocular[e.g., by eye drop], pulmonary [e.g., by oral or nasal inhalation],buccal, sublingual, rectal [e.g., by suppository], and vaginal [e.g., bysuppository]). Topical formulations can be designed to produce a localor systemic therapeutic effect.

As an example, formulations of NR/NAR derivatives suitable for oraladministration can be presented as, e.g., boluses; capsules (includingpush-fit capsules and soft capsules), tablets, pills, cachets orlozenges; as powders or granules; as semisolids, electuaries, pastes orgels; as solutions or suspensions in an aqueous liquid or/and anon-aqueous liquid; or as oil-in-water liquid emulsions or water-in-oilliquid emulsions.

Push-fit capsules or two-piece hard gelatin capsules can contain one ormore NR/NAR derivatives in admixture with, e.g., a filler or inert soliddiluent (e.g., calcium carbonate, calcium phosphate, kaolin or lactose),a binder (e.g., a starch), a glidant or lubricant (e.g., talc ormagnesium stearate), and a disintegrant (e.g., crospovidone), andoptionally a stabilizer or/and a preservative. For soft capsules orsingle-piece gelatin capsules, one or more NR/NAR derivatives can bedissolved or suspended in a suitable liquid (e.g., liquid polyethyleneglycol or an oil medium, such as a fatty oil, peanut oil, olive oil orliquid paraffin), and the liquid-filled capsules can contain one or moreother liquid excipients or/and semi-solid excipients, such as astabilizer or/and an amphiphilic agent (e.g., a fatty acid ester ofglycerol, propylene glycol or sorbitol).

Tablets can contain one or more NR/NAR derivatives in admixture with,e.g., a filler or inert diluent (e.g., calcium carbonate, calciumphosphate, lactose, mannitol or microcrystalline cellulose), a bindingagent (e.g., a starch, gelatin, acacia, alginic acid or a salt thereof,or microcrystalline cellulose), a lubricating agent (e.g., stearic acid,magnesium stearate, talc or silicon dioxide), and a disintegrating agent(e.g., crospovidone, croscarmellose sodium or colloidal silica), andoptionally a surfactant (e.g., sodium lauryl sulfate). The tablets canbe uncoated or can be coated with, e.g., an enteric coating thatprotects the active ingredient from the acidic environment of thestomach, or with a material that delays disintegration and absorption ofthe active ingredient in the gastrointestinal (GI) tract and therebyprovides a sustained action over a longer time period.

Compositions for oral administration can also be formulated as solutionsor suspensions in an aqueous liquid and/or a non-aqueous liquid, or asoil-in-water liquid emulsions or water-in-oil liquid emulsions.Dispersible powder or granules of one or more NR/NAR derivatives can bemixed with any suitable combination of an aqueous liquid, an organicsolvent or/and an oil and any suitable excipients (e.g., any combinationof a dispersing agent, a wetting agent, a suspending agent, anemulsifying agent or/and a preservative) to form a solution, suspensionor emulsion.

NR and NAR derivatives can also be formulated for parenteraladministration by, e.g., injection or infusion to circumvent GIabsorption and first-pass metabolism. An exemplary parenteral route isintravenous. Additional advantages of intravenous administration includedirect administration of a therapeutic agent into systemic circulationto achieve a rapid systemic effect, and the ability to administer theagent continuously or/and in a large volume if desired. Formulations forinjection or infusion can be in the form of, e.g., solutions,suspensions or emulsions in oily or aqueous vehicles, and can containexcipients such as suspending agents, dispersing agents or/andstabilizing agents. For example, aqueous (e.g., saline) or non-aqueous(e.g., oily) sterile injection solutions can contain one or more NR/NARderivatives along with excipients such as an antioxidant, a buffer, abacteriostat and solutes that render the formulation isotonic with theblood of the subject. Aqueous or non-aqueous sterile suspensions cancontain one or more NR/NAR derivatives along with excipients such as asuspending agent and a thickening agent, and optionally a stabilizer andan agent that increases the solubility of the NR/NAR derivative(s) toallow for the preparation of a more concentrated solution or suspension.As another example, a sterile aqueous solution for injection or infusion(e.g., subcutaneously or intravenously) can contain one or more NR/NARderivatives, sodium chloride, a buffering agent (e.g., sodium citrate),a preservative (e.g., meta-cresol), and optionally a base (e.g., NaOH)or/and an acid (e.g., HCl) to adjust pH.

In some embodiments, a composition for parenteral (e.g. intravenous)administration comprises a complex of an NR or NAR derivative with adendrimer [e.g., a poly(amidoamine) (PAMAM) dendrimer], which can be,e.g., in an aqueous solution or a colloidal liposomal formulation. As anillustrative example, an NR or NAR derivative can be combined with adendrimer (e.g., a PAMAM dendrimer) by encapsulation (e.g., thedendrimer forms a micelle encapsulating the NR or NAR derivative),electrostatic or ionic interaction, or covalent conjugation using, e.g.,an enzyme-cleavable linker (e.g., Gly-Phe-Leu-Gly). The dendrimer canoptionally have one or more moieties that target the dendrimer-NR/NARderivative complex to specific organ(s), tissue(s), cell type(s) ororganelle(s), such as the liver, tumor/cancer cells or mitochondria. Forexample, the dendrimer can optionally have one or moreN-acetylgalactosamine (GalNAc) moieties, which can target thedendrimer-containing composition to the liver by binding toasialoglycoprotein receptors on hepatocytes for treatment of, e.g., aliver or metabolic disorder. Such a dendrimer-containing composition canalso be formulated for oral administration or other modes of parenteraladministration (e.g., subcutaneous, intramuscular, intrathecal ortopical).

For topical administration, one or more NR/NAR derivatives can beformulated as, e.g., a buccal or sublingual tablet or pill. Advantagesof a buccal or sublingual tablet or pill include avoidance of GIabsorption and first-pass metabolism, and rapid absorption into systemiccirculation. A buccal or sublingual tablet or pill can be designed toprovide faster release of the NR/NAR derivative(s) for more rapid uptakeinto systemic circulation. A buccal or sublingual tablet or pill cancontain suitable excipients, including without limitation anycombination of fillers and diluents (e.g., mannitol and sorbitol),binding agents (e.g., sodium carbonate), wetting agents (e.g., sodiumcarbonate), disintegrants (e.g., crospovidone and croscarmellosesodium), lubricants (e.g., silicon dioxide [including colloidal silicondioxide] and sodium stearyl fumarate), stabilizers (e.g., sodiumbicarbonate), flavoring agents (e.g., spearmint flavor), sweeteningagents (e.g., sucralose), and coloring agents (e.g., yellow iron oxide).

For topical administration, NR and NAR derivatives can also beformulated for intranasal administration. The nasal mucosa provides abig surface area, a porous endothelium, a highly vascular subepitheliallayer and a high absorption rate, and hence allows for highbioavailability. Moreover, intranasal administration avoids first-passmetabolism and can introduce a significant concentration of the activeingredient to the central nervous system (CNS). An intranasalformulation can comprise one or more NR/NAR derivatives along withexcipients, such as a solubility enhancer (e.g., propylene glycol), ahumectant (e.g., mannitol or sorbitol), a buffer and water, andoptionally a preservative (e.g., benzalkonium chloride), a mucoadhesiveagent (e.g., hydroxyethylcellulose) or/and a penetration enhancer. Anintranasal solution or suspension formulation can be administered to thenasal cavity by any suitable means, including but not limited to adropper, a pipette, or spray using, e.g., a metering atomizing spraypump.

An additional mode of topical administration of NR and NAR derivativesis pulmonary, including by oral inhalation and nasal inhalation. Thelungs serve as a portal to the systemic circulation. Advantages ofpulmonary drug delivery include, for example: 1) avoidance of first-passhepatic metabolism; 2) fast drug action; 3) large surface area of thealveolar region for absorption, high permeability of the lungs (thinair-blood barrier), and profuse vasculature of the airways; 4) reducedextracellular enzyme levels compared to the GI tract due to the largealveolar surface area; and 5) smaller doses to achieve equivalenttherapeutic effect compared to other oral routes, and hence reducedsystemic side effects. Oral inhalation can also enable more rapid actionof a drug in the CNS. An advantage of oral inhalation over nasalinhalation includes deeper penetration/deposition of the drug into thelungs. Oral or nasal inhalation can be achieved by means of, e.g., ametered-dose inhaler, a dry powder inhaler or a nebulizer, as is knownin the art. In certain embodiments, a sterile aqueous solution for oralinhalation contains one or more NR/NAR derivatives, sodium chloride, abuffering agent (e.g., sodium citrate), optionally a preservative (e.g.,meta-cresol), and optionally a base (e.g., NaOH) or/and an acid (e.g.,HCl) to adjust pH.

Topical formulations for application to the skin or mucosa can be usefulfor transdermal or transmucosal administration of a drug into theunderlying tissue or/and the blood for systemic distribution. Advantagesof topical administration can include circumvention of GI absorption andfirst-pass metabolism, delivery of a drug with a short half-life and loworal bioavailability, more controlled and sustained release of the drug,a more uniform plasma dosing or delivery profile of the drug, lessfrequent dosing of the drug, less side effects, minimal or noinvasiveness, ease of self-administration, and increased patientcompliance.

In general, compositions suitable for topical administration includewithout limitation liquid or semi-liquid preparations such as sprays,gels, liniments and lotions, oil-in-water or water-in-oil emulsions suchas creams, foams, ointments and pastes, and solutions or suspensionssuch as drops (e.g., eye drops, nose drops and ear drops). In someembodiments, a topical composition comprises a drug dissolved, dispersedor suspended in a carrier. The carrier can be in the form of, e.g., asolution, a suspension, an emulsion, an ointment or a gel base, and cancontain, e.g., petrolatum, lanolin, a wax (e.g., bee wax), mineral oil,a long-chain alcohol, polyethylene glycol or polypropylene glycol, or adiluent (e.g., water or/and an alcohol [e.g., ethanol or propyleneglycol]), or any combination thereof. A solvent such as an alcohol canbe used to solubilize the drug. A topical composition can contain any ofa variety of excipients, such as a gelling agent, an emulsifier, athickening agent, a buffer, a stabilizer, an antioxidant, apreservative, a chemical permeation enhancer (CPE) or anirritation-mitigating agent, or any combination thereof. A topicalcomposition can include, or a topical formulation can be administered bymeans of, e.g., a transdermal or transmucosal delivery device, such as atransdermal patch, a microneedle patch or an iontophoresis device. Atopical composition can deliver a drug transdermally or transmucosallyvia a concentration gradient (with or without the use of a CPE) or anactive mechanism (e.g., iontophoresis or microneedles).

For transdermal or transmucosal administration, in some embodiments atopical composition comprises a chemical penetration enhancer (CPE) thatincreases permeation of a drug across the skin or mucosa into theunderlying tissue or/and systemic circulation. Examples of CPEs includewithout limitation alcohols and fatty alcohols (e.g., methanol, ethanol,isopropyl alcohol, pentanol, lauryl alcohol, oleyl alcohol, benzylalcohol, diethylene glycol mono-ethyl ether, propylene glycol,dipropylene glycol, polyethylene glycol and glycerol); fatty acids(e.g., capric acid, lauric acid, myristic acid, oleic acid, linoleicacid and linolenic acid); esters, fatty alcohol esters and fatty acidesters (e.g., ethyl acetate, methyl laurate, isopropyl myristate,isopropyl palmitate, methyl oleate, ethyl oleate, propylene glycolmono-oleate, glycerol mono-oleate, triacetin and pentadecalactone);hydroxyl-containing esters, fatty alcohol esters and fatty acid esters(e.g., lauryl lactate, glyceryl/glycerol monolaurate, glycerol monoleate[mono-olein], sorbitan oleate and octyl salicylate); amides, fatty amineamides and fatty acid amides (e.g., urea, dimethylformamide,dimethylacetamide, diethylacetamide, diethyltoluamide, N-lauroylsarcosine, 1-dodecylazacycloheptane-2-one [laurocapram or Azone®],Azone-related compounds, and pyrrolidone compounds [e.g., 2-pyrrolidoneand N-methyl-2-pyrrolidone]); and ionic and non-ionic surfactants (e.g.,cetyltrimethylammonium bromide, sodium laurate, sodium laureth sulfate[sodium lauryl ether sulfate], sodium cholate, sodium lauroylsarcosinate, N-lauroyl sarcosine, sorbitan monolaurate, Brij®surfactants, Pluronic® surfactants, Tween® surfactants, saponins, alkylglycosides, and fatty ether and fatty ester saccharides). US2007/0269379 provides an extensive list of CPEs.

In some embodiments, the CPE includes a surfactant. In certainembodiments, the CPE includes two or more surfactants, such as anon-ionic surfactant (e.g., sorbitan monolaurate or N-auroyl sarcosine)and an ionic surfactant (e.g., an anionic surfactant such as sodiumlauroyl sarcosinate). In other embodiments, the CPE includes asurfactant (e.g., an anionic surfactant such as sodium laureth sulfate)and an aromatic compound (e.g., 1-phenylpiperazine). Such combinationsof CPEs can greatly enhance permeation of a drug through the skin with alow potential for skin irritation.

For transmucosal administration, in certain embodiments the CPE is orincludes an alkyl glycoside (e.g., a 1-O or S—C₈-C₂₀ alkyl glycosidesuch as the corresponding glucoside, galactoside, mannoside, lactoside,maltoside [e.g., dodecyl, tridecyl or tetradecyl maltoside], melibiosideor sucroside [e.g., dodecyl sucrose]), or a fatty ether or fatty estersaccharide (e.g., a C₈-C₂₀ alkyl ether or ester saccharide such as thecorresponding glucoside, galactoside, mannoside, lactoside, maltoside,melibioside, sucroside [e.g., sucrose monododecanoate] or trehaloside).

In some embodiments, one or more NR/NAR derivatives are administered viaa transdermal patch. In certain embodiments, a transdermal patch is areservoir-type patch comprising an impermeable backing layer/film, aliquid- or gel-based drug reservoir, a semi-permeable membrane thatcontrols drug release, and a skin-contacting adhesive layer. Thesemi-permeable membrane can be composed of, e.g., a suitable polymericmaterial such as cellulose nitrate or acetate, polyisobutene,polypropylene, polyvinyl acetate or a polycarbonate. In otherembodiments, a transdermal patch is a drug-in-adhesive patch comprisingan impermeable backing layer/film and a skin-contacting adhesive layerincorporating the drug in a polymeric or viscous adhesive. The adhesiveof the drug-loaded, skin-contacting adhesive layer can be, e.g., apressure-sensitive adhesive (PSA), such as a PSA composed of an acrylicpolymer (e.g., polyacrylate), a polyalkylene (e.g., polyisobutylene) ora silicone-based polymer (e.g., silicone-2675 or silicone-2920).Transdermal drug-delivery systems, including patches, can be designed toprovide controlled and prolonged release of a drug over a period ofabout 1 week, 2 weeks, 3 weeks, 1 month or longer.

In some embodiments, one or more NR/NAR derivatives are delivered from asustained-release composition. As used herein, the term“sustained-release composition” encompasses sustained-release,prolonged-release, extended-release, delayed-release and slow-releasecompositions, systems and devices. A sustained-release composition canalso be designed to be controlled-release. Advantages of asustained-release composition include without limitation a more uniformblood level of the drug (e.g., avoidance of wide peak-to-troughfluctuations), delivery of a therapeutically effective amount of thedrug over a prolonged time period, reduced frequency of administration,and reduced side effects (e.g., avoidance of a drug overdose). Incertain embodiments, a sustained-release composition delivers one ormore NR/NAR derivatives over a period of at least about 2 days, 3 days,1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months or longer. In someembodiments, a sustained-release composition is a drug-encapsulationsystem, such as nanoparticles, microparticles or a capsule made of,e.g., a biodegradable polymer or/and a hydrogel. In certain embodiments,a sustained-release composition comprises a hydrogel. Non-limitingexamples of polymers of which a hydrogel can be composed includepolyvinyl alcohol, acrylate polymers (e.g., sodium polyacrylate), andother homopolymers and copolymers having a relatively large number ofhydrophilic groups (e.g., hydroxyl or/and carboxylate groups). In otherembodiments, a sustained-release drug-encapsulation system comprises amembrane-enclosed reservoir, wherein the reservoir contains a drug andthe membrane is permeable to the drug. Such a drug-delivery system canbe in the form of, e.g., a transdermal patch.

In certain embodiments, a sustained-release composition is an oraldosage form, such as a tablet or capsule. For example, a drug can beembedded in an insoluble porous matrix such that the dissolving drugmust make its way out of the matrix before it can be absorbed throughthe GI tract. Alternatively, a drug can be embedded in a matrix thatswells to form a gel through which the drug exits. Sustained release canalso be achieved by way of a single-layer or multi-layer osmoticcontrolled-release oral delivery system (OROS). An OROS is a tablet witha semi-permeable outer membrane and one or more small laser-drilledholes in it. As the tablet passes through the body, water is absorbedthrough the semi-permeable membrane via osmosis, and the resultingosmotic pressure pushes the drug out through the hole(s) in the tabletand into the GI tract where it can be absorbed.

In further embodiments, a sustained-release composition is formulated aspolymeric nanoparticles or microparticles, which can be delivered, e.g.,by injection or inhalation or as an implant (e.g., a depot). In someembodiments, the polymeric implant or polymeric nanoparticles ormicroparticles are composed of a biodegradable polymer. In certainembodiments, the biodegradable polymer comprises lactic acid or/andglycolic acid [e.g., an L-lactic acid-based copolymer, such aspoly(L-lactide-co-glycolide) or poly(L-lacticacid-co-D,L-2-hydroxyoctanoic acid)]. For instance, biodegradablepolymeric microspheres composed of polylactic acid or/and polyglycolicacid can serve as sustained-release pulmonary drug-delivery systems. Thebiodegradable polymer of the polymeric implant or polymericnanoparticles or microparticles can be selected so that the polymersubstantially completely degrades around the time the period oftreatment is expected to end, and so that the byproducts of thepolymer's degradation, like the polymer, are biocompatible.

In some embodiments, a sustained-release composition comprises awater-soluble polymer [e.g., poly(DL-lactide)] encapsulating an NR orNAR derivative complexed with or conjugated to a dendrimer (e.g.,PAMAM). The dendrimer can optionally have one or more moieties fortargeting to specific organ(s), tissue(s), cell type(s) or organelle(s),such as one or more N-acetylgalactosamine moieties for targeting to theliver for treatment of, e.g., a liver or metabolic disorder.

For a delayed or sustained release of one or more NR/NAR derivatives, acomposition can also be formulated as a depot that can be implanted inor injected into a subject, e.g., intramuscularly or subcutaneously. Adepot formulation can be designed to deliver an NR or NAR derivativeover a longer period of time, e.g., over a period of at least about 1week, 2 weeks, 3 weeks, 1 month, 6 weeks, 2 months, 3 months or longer.For example, an NR or NAR derivative can be formulated with a polymericmaterial (e.g., polyethylene glycol [PEG], polylactic acid [PLA] orpolyglycolic acid [PGA], or a copolymer thereof [e.g., PLGA]), ahydrophobic material (e.g., as an emulsion in an oil) or/and anion-exchange resin, or as a sparingly soluble derivative (e.g., asparingly soluble salt). As an illustrative example, an NR or NARderivative can be incorporated or embedded in sustained-releasemicroparticles composed of PLGA and formulated as a monthly depot.

In some embodiments, a pharmaceutical composition containing one or moreNR/NAR derivatives is a controlled-release composition. Acontrolled-release composition can deliver a drug in a controlledtime-dependent manner, and can be designed to deliver the drug, e.g.,with delay after administration or/and for a prolonged time period. Acontrolled-release composition can also be designed to achieveparticular profiles of dissolution of the drug in particularenvironments (e.g., in the GI tract) and to improve pharmacokinetics(e.g., bioavailability) of the drug. In certain embodiments, acontrolled-release composition is administered once daily, once everytwo or three days, twice weekly or once weekly. In certain embodiments,a controlled-release composition is enterically coated for oraladministration.

In some embodiments, a capsule for oral administration contains aplurality of pellets, each pellet comprising a pellet core containingone or more NR/NAR derivatives and a controlled-release coatingsurrounding the pellet core. The one or more NR/NAR derivatives can be,e.g., dispersed in a solid or semi-solid pellet core or in a drug layercoating the pellet core. In certain embodiment, the controlled-releasecoating comprises ethyl cellulose; povidone or/and hydroxypropyl methylcellulose; and a plasticizer.

In addition, pharmaceutical compositions comprising one or more NR/NARderivatives can be formulated as, e.g., liposomes, micelles (e.g., thosecomposed of biodegradable natural or/and synthetic polymers, such aslactosomes), nanoparticles, microparticles or microspheres, whether ornot designed for sustained release. For example, liposomes can be usedas a sustained-release pulmonary drug-delivery system that delivers adrug to the alveolar surface for treatment of a lung disorder or asystemic disorder.

In some embodiments, liposomes or micelles are composed of one or morephospholipids. Phospholipids include without limitation phosphatidicacids (e.g., DEPA, DLPA, DMPA, DOPA, DPPA and DSPA),phosphatidylcholines (e.g., DDPC, DEPC, DLPC, DLOPC, DMPC, DOPC, DPPC,DSPC, MPPC, MSPC, PLPC, PMPC, POPC, PSPC, SMPC, SOPC and SPPC),phosphatidylethanolamines (e.g., DEPE, DLPE, DMPE, DOPE, DPPE, DSPE andPOPE), phosphatidylglycerols (e.g., DEPG, DLPG, DMPG, DOPG, DPPG, DSPGand POPG), phosphatidylserines (e.g., DLPS, DMPS, DOPS, DPPS and DSPS),and salts (e.g., sodium and ammonium salts) thereof. In certainembodiments, liposomes or micelles are composed of one or morephosphatidylcholines. Liposomes have a hydrophilic core, so liposomesare particularly suited for delivery of more hydrophilic drugs, whereasmicelles have a hydrophobic core, so micelles are particularly suitedfor delivery of more hydrophobic drugs. Liposomes and micelles canpermeate across biological membranes. Liposomes and micelles composed ofa fusogenic lipid (e.g., DPPG) can fuse with the plasma membrane ofcells and thereby deliver a drug into those cells. Liposomes andmicelles can provide sustained release of a drug based in part on therate of degradation of the liposomes and micelles.

Pharmaceutical compositions can be manufactured in any suitable mannerknown in the art, e.g., by means of conventional mixing, dissolving,suspending, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or compressing processes.

A pharmaceutical composition can be presented in unit dosage form as asingle dose wherein all active and inactive ingredients are combined ina suitable system, and components do not need to be mixed to form thecomposition to be administered. A unit dosage form generally contains atherapeutically effective dose of the drug, but can contain anappropriate fraction thereof so that taking multiple unit dosage formsachieves the therapeutically effective dose. Representative examples ofa unit dosage form include a tablet, capsule or pill for oral uptake; asolution in a pre-filled syringe of a single-use pen or a pen with adose counter for parenteral (e.g., intravenous, subcutaneous orintramuscular) injection; a capsule, cartridge or blister pre-loaded inor manually loaded into an inhaler; and a reservoir-type transdermalpatch or a drug-in-adhesive patch.

Alternatively, a pharmaceutical composition can be presented as a kit inwhich the drug, excipients and carriers (e.g., solvents) are provided intwo or more separate containers (e.g., ampules, vials, tubes, bottles orsyringes) and need to be combined to form the composition to beadministered. The kit can contain instructions for storing, preparingand administering the composition (e.g., a solution to be injectedparenterally).

A kit can contain all active and inactive ingredients in unit dosageform or the active ingredient and inactive ingredients in two or moreseparate containers, and can contain instructions for administering orusing the pharmaceutical composition to treat a medical condition. A kitcan further contain a device for delivering the composition, such as aninjection pen, an inhaler or a transdermal patch.

In some embodiments, a kit contains one or more NR/NAR derivatives or apharmaceutical composition comprising the same, and instructions foradministering or using the one or more NR/NAR derivatives or thepharmaceutical composition comprising the same to treat a disease,disorder or condition described herein. In certain embodiments, a kitcontains a compound of Formula II or a compound of Formula IV. Infurther embodiments, a kit contains a compound of Formula I and acompound of Formula II, or a compound of Formula III and a compound ofFormula IV.

The description and all of the embodiments relating to pharmaceuticalcompositions and kits comprising the NR and NAR derivatives describedherein also apply to pharmaceutical compositions and kits comprisingother NR and NAR derivatives (e.g., NRTA, NRHTA, NARTA and NARHTA) andto pharmaceutical compositions and kits comprising NR, NRH, NAR or/andNARH.

Uses of NR and NAR Derivatives

The NR and NAR derivatives described herein can increase NAD⁺ levels ina subject, including in cells, tissues and organs and potentially in theblood. By increasing NAD⁺ levels, the NR and NAR derivatives can improvemitochondrial and cellular function (e.g., DNA repair) in target cells,tissues and organs and can improve cell viability. Benefits of improvedmitochondrial function include without limitation enhanced mitochondrialoxidative metabolism, mitochondrial respiration, ATP production,mitochondrial membrane potential, mitophagy (autophagy of defectivemitochondria) and mitochondrial biogenesis, and reduced levels ofreactive oxygen species (ROS). For example, higher NAD⁺ levels increasethe activity of the mitochondrial NAD-dependent deacetylases sirtuin-1(SIRT1) and sirtuin-3 (SIRT3). SIRT1 promotes autophagy of defectivemitochondria, stimulates mitochondrial biogenesis, inhibits thepro-inflammatory transcription factor NF-κB, increases insulinsensitivity, and mimics the effects of calorie restriction. Stimulationof SIRT3 activity increases mitochodrial biogenesis, increases cellularrespiration and energy production, reduces ROS levels (e.g., bystimulating mitochondrial superoxide dismutase 2 [SOD2]), promotes cellsurvival during genotoxic stress, functions as a mitochondrial tumorsuppressor, increases insulin sensitivity and sensitizes cells toglucose uptake, and mimics calorie restriction and exercise. ImprovedDNA repair reduces cell damage and enhances cell function, health andlifespan. In addition, prevention of NAD⁺ depletion protects neurons inexcitotoxic or ischemic conditions.

Therefore, the NR and NAR derivatives are useful for treating pellagra,mitochondrial diseases, mitochondria-related diseases and conditions,diseases and conditions associated with acute NAD⁺ depletion resultingfrom DNA damage, aging-related disorders and conditions, skin disordersand conditions, and other types of disorders and conditions. In someembodiments, a single NR or NAR derivative (e.g., a compound of FormulaII or IV) is used to treat a disease/disorder or condition disclosedherein or to bring about a biological effect disclosed herein (e.g.,increase NAD⁺ level, enhance mitochondrial or cellular function, improvemetabolic health or cell viability, or provide cytoprotection). In otherembodiments, a compound of Formula I and a compound of Formula II, or acompound of Formula III and a compound of Formula IV, are used to treata disease/disorder or condition disclosed herein or to bring about abiological effect disclosed herein. The use of both an oxidized form ofan NR or NAR derivative (Formula I or III) and a reduced form of an NRor NAR derivative (Formula II or IV) can have an additive effect orpotentially a synergistic effect. In further embodiments, one or moreNR/NAR derivatives disclosed herein are used in conjunction with NR,NRH, NAR or NARH, or any combination thereof, to treat adisease/disorder or condition disclosed herein or to bring about abiological effect disclosed herein. The use of an NR or NAR derivativeplus NR, NRH, NAR or NARH can have an additive effect or potentially asynergistic effect. A single NR or NAR derivative can be administered inthe form of, e.g., a pharmaceutical or cosmetic composition. If, e.g.,two NR/NAR derivatives are utilized, they can be administered in thesame composition or in different compositions.

The NR and NAR derivatives have other beneficial effects. For example,they can enhance immune function in peripheral blood mononuclear cells(e.g., T-cells, B-cells, macrophages and natural killer [NK] cells)based on improved antigen recognition and proliferation as a function ofimmune surveillance. For such an application, one or more NR/NARderivatives can be employed alone, as a component of a vaccine, as acomponent of an ex vivo therapy (e.g., a CAR-T cell therapy), or as acomponent of some other therapy.

Mitochondrial diseases include without limitation mitochondrialmyopathies; limb-girdle distribution weakness; Kearns-Sayre syndrome(KSS); Pearson syndrome; Leigh syndrome; Barth syndrome; Friedreich'sataxia; neuropathy, ataxia, retinitis pigmentosa and ptosis (NARP);mitochondrial DNA depletion syndrome (Alper's disease); mitochondrialneurogastrointestinal encephalopathy (MNGIE) syndrome; mitochondrialencephalopathy, lactic acidosis and stroke-like episodes (MELAS)syndrome; myoclonic epilepsy with ragged red fibers (MERRF or Fukubarasyndrome); chronic progressive external ophthalmoplegia (CPEO); Leber'shereditary optic neuropathy (LHON); inherited forms of blindness anddeafness (e.g., diabetes mellitus and deafness); and acquired forms ofreversible or permanent hearing loss {e.g., type 2 diabetes-associatedhearing loss and hearing loss induced by ototoxic chemicals (e.g., heavymetals [e.g., lead], solvents [e.g., styrene and toluene] andasphyxiants [e.g., carbon monoxide]) and medications (e.g., loopdiuretics [e.g., bumetanide and furosemide], NSAIDs [e.g., aspirin,celecoxib, diclofenac, ibuprofen and naproxen], PDE5 inhibitors,macrolide antibiotics, aminoglycosides [e.g., gentamicin],platinum-based chemotherapeutics [e.g., carboplatin and cisplatin],paracetamol and quinine)}.

Mitochondria-related diseases and conditions include, but are notlimited to, neurodegenerative disorders, neuronal activation disorders,muscle disorders (including eye muscle disorders), fatty acid/betaoxidation disorders, metabolic disorders, inflammatory disorders,vascular disorders (including ocular vascular disorders), renaldisorders, liver disorders, tumors, cancers, male and femaleinfertility, and aging-related disorders.

Neurodegenerative disorders include without limitation dementias (e.g.,Alzheimer's disease [AD], vascular dementia, dementia with Lewy bodiesand frontotemporal dementia [Pick's disease]), motor neuron disorders(e.g., Parkinson's disease, amyotrophic lateral sclerosis [ALS or LouGehrig's disease], primary lateral sclerosis [PLS] and spinal muscularatrophy [SMA]), ataxia (e.g., spinocerebellar ataxia/degeneration,Friedreich's ataxia, ataxia-telangiectasia [Louis-Bar syndrome] andfragile X-associated tremor/ataxia syndrome [FXTAS]), dyskinesias (e.g.,cerebral palsy, chorea, dystonia and essential tremor), cognitive-motordisorders (e.g., corticobasal degeneration, Huntington's disease [HD]and Parkinson-plus syndromes), chorea-acanthocytosis, retinal neuronaldegeneration, Batten disease, DNA-repair syndromes (e.g., Cockaynesyndrome), and prion diseases (e.g., Creutzfeldt-Jakob disease).

Neuronal activation disorders include without limitationneurodegenerative disorders (e.g., ALS), neuronal injuries (includingtraumatic and mechanical injuries to the brain, the spinal cord and theperipheral nervous system [PNS], and excitotoxic neuronal injuries suchas those associated with seizures and ischemia), nerve lesions,neuropathies (e.g., peripheral neuropathies [e.g., Charcot-Marie-Toothdisease], mononeuropathies [e.g., those caused by compression, traumaticinjury, cumulative trauma, ischemia, inflammation, connective tissuedisorders and neoplasms], polyneuropathies [e.g., chronic inflammatorydemyelinating polyneuropathy], brachial plexus neuropathies, diabeticneuropathies [e.g. third nerve palsy, mononeuropathy, mononeuropathymultiplex, autonomic neuropathy, thoracoabdominal neuropathy anddiabetic amyotrophy], and chemotherapy-induced neuropathies), autoimmunenerve disorders (e.g., multiple sclerosis, Guillain-Barré syndrome,Lambert-Eaton myasthenic syndrome and myasthenia gravis),neuroinflammation, tardy ulnar nerve palsy, and toxic myoneuraldisorder.

Muscle disorders include, but are not limited to, muscle structuredisorders, muscle mass disorders and muscle fatigue disorders. Musclestructure disorders include without limitation myopathies (e.g.,cardiomyopathy), neuromuscular degeneration, muscular dystrophy (MD),congenital MD, distal MD, Duchenne MD, Becker MD, Emery-Dreifuss MD,limb-girdle MD, myotonic MD, facioscapulohumeral MD, oculopharyngeal MD,Bethlem myopathy, central core disease, congenital fiber typedisproportion, hyaline body myopathy, muscle sodium channel disorders,myotonic dystrophy, myotonic chondrodystrophy, myotubular myopathy,nemaline body disease, myositis, sarcopenia, rhabdomyolysis, and stressurinary incontinence. Muscle mass disorders include without limitationmuscle atrophy, cachexia, cartilage degeneration, cerebral palsy,compartment syndrome, critical illness myopathy, inclusion bodymyositis, sarcopenia, steroid myopathy, and systemic lupus erythematosus(SLE). Muscle fatigue disorders include without limitation chronicfatigue syndrome, fibromyalgia, thyrotoxic myopathy, lipid-storagemyopathy, Friedreich's ataxia, glycogen storage diseases (e.g., Pompedisease), intermittent claudication, MELAS, and mucopolysaccharidosis.

Eye muscle disorders include, but are not limited to, disorders ofrefraction, disorders of accommodation, disorders of refraction andaccommodation, strabismus, progressive external ophthalmoplegia,internal ophthalmoplegia, esotropia, exotropia, hypermetropia, myopia,astigmatism, anisometropia, and presbyopia.

Fatty acid/beta oxidation disorders include without limitation systemiccarnitine transporter deficiency, carnitine palmitoyl transferase (CPT)II deficiency, very long-chain acyl-CoA dehydrogenase (LCHAD or VLCAD)deficiency, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency,short-chain acyl-CoA dehydrogenase (SCAD) deficiency, trifunctionalenzyme deficiency, and riboflavin-responsive disorders of β-oxidation(RR-MADD).

Metabolic disorders include without limitation lipodystrophy (geneticand acquired), metabolic syndrome, hyperglycemia, impaired glucosetolerance (including prediabetes and diabetes), insulin resistance,hyperinsulinism, diabetes mellitus (including types 1 and 2), diabeticcomplications (e.g., diabetic neuropathy and diabetic retinopathy),obesity, dyslipidemia, hyperlipidemia, hyperchlolesterolemia,non-high-density lipoprotein (HDL) hypercholesterolemia, low-densitylipoprotein (LDL) hypercholesterolemia, HDL hypocholesterolemia,hypertriglyceridemia, dyslipoproteinemia, very low-density lipoprotein(VLDL) hyperproteinemia, apolipoprotein A-I hypoproteinemia,hypertension, cardiovascular diseases (e.g., cardiomyopathy [e.g.,metabolic cardiomyopathy], cardiac insufficiency, myocardial infarction,atherosclerosis, thrombotic disorders and peripheral vascular diseases),inflammatory disorders (e.g., arthritis, asthma and pancreatitis), liverdisorders (e.g., non-alcoholic fatty liver disease [NAFLD] andnon-alcoholic steatohepatitis [NASH]), kidney disorders (e.g., chronickidney disease), gastrointestinal (GI) disorders (e.g., Crohn's disease,hypersensitive intestine syndrome, ulcerative colitis and dyspepsia),neurodegenerative disorders (e.g., Alzheimer disease), demyelinatingdisorders (e.g., multiple sclerosis), skin disorders (e.g., acne,dermatitis, psoriasis and skin aging), trichosis, adrenalleukodystrophy, edema, ketoacidosis, sexual (e.g., erectile)dysfunction, and tumors and cancers.

In some embodiments, the NR and NAR derivatives are used to treathyperglycemia, impaired glucose tolerance and insulin resistance anddisorders and conditions related thereto, including prediabetes, types 1and 2 diabetes, and obesity-related disorders and conditions. The NR andNAR derivatives stimulate SIRT1 and SIRT3 activity, either of whichincreases insulin sensitivity, sensitizes cells to glucose uptake andmimics calorie restriction. Increased insulin sensitivity can reduceinsulin production. Hyperinsulinemia promotes differentiation ofpreadipocytes into adipocytes. Therefore, reduction of blood insulinlevel can inhibit fat cell differentiation and adipogenesis and thus canhave therapeutic effects on obesity-related disorders and conditions,including but not limited to dyslipogenesis, hyperlipidemia,hypercholesterolemia, atherosclerosis, metabolic syndrome, lipodystrophyand hypertension.

ROS incite inflammation, in part by activating transcriptions factorssuch as NF-κB that increase the expression of pro-inflammatorycytokines. The NR and NAR derivatives disclosed herein can reduce ROSlevels by, e.g., stimulating SIRT3 activity. Moreover, the NR and NARderivatives can increase the activity of NAD-dependent deacetylasesirtuin-1 (SIRT1), which inhibits NF-κB. NF-κB is the main promoter ofthe transcription of genes encoding pro-inflammatory cytokines. Thus,the NR and NAR derivatives are useful for treating inflammatorydisorders. Inflammatory disorders include without limitationneuroinflammation (e.g., neuritis [e.g., ocular neuritis and peripheralneuritis], Alzheimer's disease and multiple sclerosis), GI disorders(e.g., gastritis, necrotizing enterocolitis, mucous colitis, ulcerativecolitis, inflammatory bowel disease, irritable bowel syndrome, Crohn'sdisease and celiac disease), peritonitis, pancreatitis (acute andchronic), glomerulonephritis, liver disorders (e.g., hepatitis,non-alcoholic and alcoholic steatohepatitis, cirrhosis and chronic liverdisease), multiple organ dysfunction syndrome (e.g., secondary tosepticemia or trauma), metabolic disorders (e.g., diabetes [e.g., types1 and 2 diabetes and juvenile-onset diabetes] and metabolic syndrome),cardiac disorders (e.g., myocarditis and myocardial infarction),vascular disorders (e.g., vasculitis, atherosclerosis, stroke,peripheral artery disease and shock), reperfusion injury (e.g., due tomyocardial ischemia, cerebral ischemia, cardiopulmonary bypass or kidneydialysis), airway disorders (e.g., rhinitis [e.g., allergic rhinitis],esophagitis, asthma, acute respiratory distress syndrome, bronchitis[e.g., chronic bronchitis], pneumonitis and chronic obstructivepulmonary disease [COPD]), arthritis (e.g., osteoarthritis [degenerativejoint disease], rheumatoid arthritis, psoriatic arthritis, goutyarthritis, axial spondyloarthritis, ankylosing spondylitis and juvenilearthritis), skin disorders (e.g., dermatitis/eczema, psoriasis,urticaria, dermatosis with acute inflammatory components, and sunburn),Sjögren syndrome, eye disorders (e.g., conjunctivitis, retinitis andAMD), SLE, hypertension and dysmenorrhea (menstrual cramps).

Inflammation is a major stimulant of fibrosis. In part by reducinginflammation, the NR and NAR derivatives disclosed herein are useful fortreating fibrotic disorders. Fibrotic disorders include withoutlimitation cardiomyopathy (e.g., diabetic cardiomyopathy and uremiccardiomyopathy), cardiac fibrosis, myocardial fibrosis,collagen-vascular diseases (e.g., arterial stiffness and vascularfibrosis), atherosclerosis, chronic heart failure, diabetic nephropathy,renal fibrosis, chronic kidney disease (e.g., chronic renal failure),liver fibrosis, cirrhosis, NASH, chronic liver disease, liver failure(e.g., chronic liver failure), pulmonary fibrosis (e.g., idiopathicpulmonary fibrosis and radiation-induced pulmonary fibrosis), cysticfibrosis, and scleroderma (e.g., localized scleroderma and systemicscleroderma/systemic sclerosis)

Vascular disorders include, but are not limited to, cardiovasculardiseases (e.g., myocardial ischemia, ischemia-reperfusion injury [IRI],arteriosclerosis and atherosclerosis), cerebrovascular diseases (e.g.,cerebral ischemia and IRI), peripheral vascular diseases (e.g.,peripheral vascular insufficiency, peripheral artery disease,intermittent/vascular claudication, critical limb ischemia, peripheralartery occlusive disease, and peripheral obliterative arteriopathy),thrombotic/blood clotting/hemostatic disorders (e.g., disseminatedintravascular coagulation, deep vein thrombosis, thrombophilia [e.g.,due to anti-thrombin III deficiency, protein S deficiency, protein Cdeficiency or resistance to activated protein C], thromboticthrombocytopenic purpura, heparin-induced thrombocytopenia,dysfibrinogenemia, atherosclerosis, arteriosclerosis, myocardialischemia/infarction, angina [e.g., unstable angina], ischemic stroke,sickle cell disease, myeloproliferative neoplasms, cancer metastasis,homocystinuria, and miscarriage), and embolism (e.g., thromboembolism,fat embolism, arterial embolism [e.g., myocardial ischemia, ischemicstroke and acute limb ischemia], and venous embolism [e.g., pulmonaryembolism]). As an illustrative example, one or more NR/NAR derivativescan be used to treat or prevent thromobosis or a thrombotic disorder,including to reduce or prevent thrombotic events or re-occlusion duringor/and after a clot-clearing intervention (e.g., a surgery such asangioplasty).

Ocular vascular disorders include without limitation retinopathy (e.g.,hypertensive retinopathy and diabetic retinopathy), macular degeneration(e.g., age-related macular degeneration [AMD]), Stargardt disease,retinal hemorrhage and glaucoma.

Renal disorders include without limitation acute nephritis, chronicnephritis, rapidly progressive nephritis, glomerulonephritis,glomerulosclerosis, hypertensive nephrosclerosis, renal ischemia, IRI,Bartter syndrome, diabetic nephropathy, acute renal failure (acutekidney injury), chronic renal failure, nephrotic syndrome, recurrenthematuria and persistent hematuria.

Liver disorders include without limitation NAFLD, NASH, alcoholic liverdisease, hepatitis (e.g., autoimmune hepatitis, hepatitis B andhepatitis C), cholestatic disorders (e.g., cholestasis, primary biliarycholangitis/cirrhosis and primary sclerosing cholangitis), liver injury,chronic liver disease, liver failure (acute and chronic), cirrhosis, andliver cancer.

Tumors (benign and malignant) and cancers include without limitationbrain tumors, spinal cord tumors, germ cell tumors, neuroendocrinetumors, carcinoid tumors, tumors and cancers associated with viralinfections (e.g., HIV and HTLV-1), carcinomas, sarcomas, and cancers ofthe digestive/gastrointestinal system, gynecological organs (e.g., thebreast), genitourinary system, musculoskeletal system, respiratorysystem, head and neck, eye, skin (e.g., melanomas), blood (e.g.,leukemias, multiple myeloma, Hodgkin's lymphomas and non-Hodgkin'slymphomas), endocrine system (e.g., hormone-dependent cancers such asbreast, ovarian, prostate and testicular cancers), neuroendocrinesystem, neurological system, and germ cells. In some embodiments, one ormore NR/NAR derivatives are used to treat a cancer of the breast, ovary,colon/large intestine, rectum, pancreas, liver, kidney, lung, prostate,brain or skin. In further embodiments, one or more NR/NAR derivativesare used to treat a hematological malignancy, such as acutelymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chroniclymphocytic leukemia (CLL), chronic myelogenous leukemia (CML),non-Hodgkin lymphoma or multiple myeloma.

Disorders relating to female infertility include without limitationpolycystic ovarian syndrome (PCOS), diminished ovarian reserve,endometriosis, and infertility caused by radiation or chemotherapy.Disorders relating to male infertility include without limitationoligospermia and spermatogenesis caused by medications.

Somatic mutations in mitochondrial DNA increase significantly with age,which can result in defective mitochondria. Moreover, respiratory chainactivity diminishes with age. Non-limiting examples of aging-relateddisorders are described below.

In some embodiments, one or more NR/NAR derivatives are used to treat amitochondria-related disease or condition selected from geneticlipodystrophy, metabolic syndrome, obesity, types 1 and 2 diabetes,NAFLD, NASH, alcoholic liver disease, autoimmune hepatitis, cholestaticliver disease, hemochromatosis, alpha-1 antitrypsin deficiency, otherhereditary inborn errors of metabolism, and renal ischemia and IRI.

Diseases and conditions characterized by acute NAD⁺ depletion due to DNAdamage include without limitation exposure to radiation (e.g., UV andionizing radiation such as X-ray), radiation or chemotherapy-induceddisorders (e.g., dermatitis, myositis, myocarditis, colitis,prostatitis, hepatitis, pneumonitis, neuropathies and bone marrowfailure), burn injuries (including first-degree burns, second-degreeburns and third-degree burns), chemical exposure with manifestation ofexfoliative dermatitis, exposure to chemical warfare agents,Stevens-Johnson syndrome, acute respiratory distress syndrome,inhalational lung injury due to smoke or chemical toxins, trauma-relatedcrush injuries (including those with bone fractures), peripheral nerveinjuries, spinal cord injuries, and contusion to internal organs (suchas the heart, lung, liver and kidney). Such diseases and conditions cangenerate a large amount of ROS such as superoxide, peroxides andhydroxyl radical, which cause DNA damage and hence cell damage or celldeath. In other words, DNA damage induced by, e.g., radiation,chemotherapy or oxidative stress can cause acute NAD⁺ depletion thatresults in systemic toxicity and systemic disorders (e.g., dermatitis,pneumonitis, bone marrow failure and neuropathies), as well as localtoxicity and local disorders. Exemplary chemical warfare agents includeblister agents (e.g., vesicants, nitrogen mustards, sulfur mustards,arsenicals and urticants [e.g., phosgene]), blood agents (e.g.,cyanide), pulmonary agents (e.g., phosgene), and nerve agents (e.g.,G-series agents [e.g., sarin and soman], GV-series agents and V-seriesagents).

Reduced NAD⁺ levels are associated with aging, which leads toaging-related metabolic dysfunction and disorders (e.g., inflammatorydisorders). For example, the expression and activity of CD38, whichrapidly degrades NAD⁺ and its precursor NMN, increase during the agingprocess. Therefore, the NR and NAR derivatives described herein areuseful for treating aging-related disorders and conditions. Furthermore,the NR and NAR derivatives described herein can extend the lifespan ofcells by, e.g., slowing or delaying the aging/senescence of cells,promoting the survival of cells, preventing apoptosis of cells,extending the proliferative capacity of cells, increasing cellularresistance to stress (e.g., oxidative stress), mimicking the effects ofcalorie restriction or promoting wound healing, or any combinationthereof. In addition, NAD repletion improves stem cell function.Aging-related disorders and conditions include, but are not limited to,aging/senescence, hypertension, eye disorders (e.g., AMD, cataracts andkeratoconjunctivitis sicca [dry eye syndrome]), hearing loss,osteoporosis, sarcopenia, dementias (e.g., Alzheimer's disease),metabolic disorders (e.g., metabolic decline, diabetes [including T1Dand T2D] and obesity), cardiovascular disorders (e.g.,arteriosclerosis), inflammatory disorders (e.g., arthritis and COPD),DNA-repair syndromes (e.g., Cockayne syndrome), and tumors and cancers.Because of their cytoprotective and antioxidant properties, for example,the NR and NAR derivatives can be used to prevent or mitigate hearingloss, including noise-induced hearing loss, trauma-induced hearing lossand progressive hearing loss syndromes.

By enhancing cell viability, providing cytoprotection or/and increasingcell lifespan, the NR and NAR derivatives of the disclosure can be usedto treat disorders characterized by cell degeneration or death. Forexample, retinal disorders characterized by cell degeneration or deathinclude, but are not limited to, AMD, retinitis pigmentosa, cone-roddystrophy/degeneration, diabetic retinopathy, Leber's congenitalamaurosis, and vision loss.

The cytoprotective NR and NAR derivatives can be used to treat otherdisorders and conditions characterized by cell degeneration or/and celldeath, including without limitation neuronal disorders (e.g.,Alzheimer's disease, Creutzfeld-Jakob disease, Parkinson's disease, ALSand multiple sclerosis), degeneration of the brain (e.g., cerebellardegeneration and traumatic brain injury), muscle disorders (e.g.,muscular dystrophies such as Duchenne MD, facioscapulohumeral MD andmyotonic dystrophy), ischemic disorders (e.g., myocardialischemia/infarction and cerebral ischemia [stroke]/infarction),atherosclerosis, myelodysplastic syndromes (e.g., aplastic anemia),hepatitis (e.g., alcoholic hepatitis, fulminant hepatitis, hepatitis A,hepatitis B, hepatitis C, hepatitis D and hepatitis E), joint disorders(e.g., osteoarthritis), skin atrophy, lichen planus, skin damage causedby UV light, graft rejections, alopecia, AIDS, and cell damage or/andcell death caused by trauma (e.g., to the brain or the spinal cord),surgery, medications, chemicals, biological and chemical toxins, andradiation (e.g., ionizing radiation such as X-ray). To prevent celldamage or/and cell death that may result from, e.g., a medicalintervention such as surgery or radiation therapy, one or more NR/NARderivatives can be administered to the subject prior to or/and shortlyafter the intervention.

In part because of their ability to protect cells from the effects ofDNA damage and to enhance cell viability and lifespan, the NR and NARderivatives described herein are useful for treating skin disorders andconditions. The skin disorders and conditions can be associated with orcaused by, e.g., natural aging, inflammation, oxidative stress or sundamage. Such skin disorders and conditions include without limitationskin wrinkles, dermatitis/eczema (e.g., atopic dermatitis, contactdermatitis [allergic and irritant], exfoliative dermatitis andseborrheic dermatitis), psoriasis (e.g., plaque psoriasis), skin damagecaused by sunlight or other light sources (e.g., sunburn, actinickeratosis and xeroderma pigmentosum), keratinization disorders,erythemas (e.g., erythema multiforme and erythema nodosum),dermatomyositis, discoid lupus erythematosus, pemphigoid (e.g., bullouspemphigoid), pemphigus (e.g., pemphigus vulgaris), epidermolysisbullosa, burns (e.g., first-degree burns, second-degree burns andthird-degree burns, and thermal burns, radiation burns, chemical burnsand electrical burns), wounds, and skin cancers.

Partly because of their cytoprotective properties, the NR and NARderivatives disclosed herein can promote donor graft preservation inorgan transplantation. Therefore, the NR and NAR derivatives can beapplied to cells, tissue or organ employed in transplantation and celltherapies, such as solid-tissue grafts, organ transplants, cellsuspensions, stem cells and bone marrow cells. The cells, tissue ororgan may be an autograft, an allograft, a syngraft or a xenograft. Thecells, tissue or organ can be treated with one or more NR/NARderivatives prior to, concurrently with or/and postadministration/implantation of the cells, tissue or organ into arecipient. The cells, tissue or organ can be treated with one or moreNR/NAR derivatives prior to removal of the cells, tissue or organ fromthe donor, ex vivo after removal of the cells, tissue or organ from thedonor, or post administration/implantation into the recipient. Forexample, the donor or/and the recipient can be treated systemically withone or more NR/NAR derivatives, or can have a subset of cells, tissue ororgan treated locally with one or more NR/NAR derivatives. In certainembodiments, the cells, tissue or organ (or the donor or/and therecipient) are treated with an additional therapeutic agent thatprolongs graft survival, such as an immunosuppressant, a cytokine or anangiogenic factor, or any combination thereof.

As an example, since enhancement of NAD⁺ levels promotes differentiationof transplanted cells, the use of one or more NR/NAR derivatives canimprove engraftment of a bone marrow transplant, which can minimizecytopenia (including neutropenia, lymphopenia, anemia andthrombocytopenia), the need for growth factors and complications ofinfection. As another example, the use of one or more NR/NAR derivativescan prevent graft versus host disease (GVHD) in an allogeneictransplant.

In some embodiments, one or more NR/NAR derivatives are used in culturemedium as a component of an ex vivo therapy, such as a chimeric antigenreceptor (CAR) T-cell therapy. A CAR-T cell therapy can be autologous orallogeneic. In certain embodiments, the ex vivo therapy utilizeshematopoietic stem cells (HSC), embryonic stem cells (ESC) orpluripotent stem cells (PSC). One or more NR/NAR derivatives can be usedto improve the yield of pancreatic endocrine cells during the finalstages of in vitro ESC and PSC differentiation into pancreaticislet-like, insulin-secreting cells.

In further embodiments, the NR and NAR derivatives are used to enhancemitochondrial or cellular function or/and cellular energy production inoocytes, postnatal female germline stem cells or/and pre-implantationembryos prior to or/and following in vitro fertilization, or followingexposure of ovaries, oocytes, postnatal female germline cells or/andpreimplantation embryos in vivo. In some embodiments, one or more NR/NARderivatives are used with a solution selected from cell culture medium,oocyte retrieval solution, oocyte washing solution, oocyte in vitromaturation medium, ovarian follicle in vitro maturation medium, oocytein vitro fertilization medium, vitrification solution andcryopreservation solution in assisted reproduction techniques such as invitro fertilization. The disclosure encompasses compositions comprisingan isolated oocyte, oogonial stem cell (OSC) or OSC progeny, and one ormore NR/NAR derivatives.

The therapeutically effective amount and the frequency of administrationof, and the length of treatment with, an NR or NAR derivative to treat adisease/disorder or condition disclosed herein may depend on variousfactors, including the nature and severity of the disease/disorder orcondition, the potency of the compound, the route of administration, theage, body weight, general health, gender and diet of the subject, andthe response of the subject to the treatment, and can be determined bythe treating physician. In some embodiments, the therapeuticallyeffective amount of an NR or NAR derivative to treat a disease/disorderor condition disclosed herein, or to bring about a biological effect(e.g., increase NAD⁺ level, enhance mitochondrial or cellular function,improve metabolic health or cell viability, or provide cytoprotection),is about 1-1000 mg, 1-100 mg, 100-500 mg or 500-1000 mg (e.g., per dayor per dose), or as deemed appropriate by the treating physician, whichcan be administered in a single dose or in divided doses. In furtherembodiments, the therapeutically effective amount of an NR or NARderivative is about 1-50 mg, 50-100 mg, 100-200 mg, 200-300 mg, 300-400mg, 400-500 mg, 500-600 mg, 600-700 mg, 700-800 mg, 800-900 mg or900-1000 mg (e.g., per day or per dose). In additional embodiments, thetherapeutically effective amount of an NR or NAR derivative is about 50mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700mg, 800 mg, 900 mg or 1000 mg (e.g., per day or per dose).

In some embodiments, the therapeutically effective amount of an NR orNAR derivative is about 100-500 mg, 100-200 mg, 200-300 mg, 300-400 mgor 400-500 mg per day, which can be administered in a single dose (e.g.,N mg once daily) or in divided doses (e.g., N/2 mg twice daily). Infurther embodiments, the therapeutically effective amount of an NR orNAR derivative is about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mgor 500 mg per day. In certain embodiments, the therapeutically effectiveamount of an NR or NAR derivative is about 200-300 mg per day, or about200 mg, 250 mg or 300 mg per day.

The therapeutically effective dose of an NR or NAR derivative can beadministered one, two or more times a day, once every two days, onceevery three days, twice a week or once a week, or as deemed appropriateby the treating physician. In certain embodiments, the therapeuticallyeffective dose of an NR or NAR derivative is administered once or twicedaily. As an illustrative example, if the therapeutically effective doseof an NR or NAR derivative is about 300 mg per day, 300 mg of thecompound can be taken once daily, or 150 mg of the compound can be takentwice daily.

Where a more rapid establishment of a therapeutic level of an NR or NARderivative is desired, such as in the treatment of anischemia-reperfusion injury, the compound can be administered under adosing schedule in which a loading dose is administered, followed by (i)one or more additional loading doses and then one or moretherapeutically effective maintenance doses, or (ii) one or moretherapeutically effective maintenance doses without an additionalloading dose, as deemed appropriate by the treating physician. In such acase, a loading dose of a drug is larger (e.g., about 1.5, 2, 3, 4 or 5times larger) than a subsequent maintenance dose and is designed toestablish a therapeutic level of the drug more quickly. The one or moretherapeutically effective maintenance doses can be any therapeuticallyeffective amount/dose described herein. In certain embodiments, theloading dose is about three times larger than the maintenance dose. Insome embodiments, a loading dose of an NR or NAR derivative isadministered on day 1 and a maintenance dose is administered on day 2and thereafter for the duration of therapy. In other embodiments, afirst loading dose of an NR or NAR derivative is administered on day 1,a second loading dose is administered on day 2, and a maintenance doseis administered on day 3 and thereafter for the duration of therapy. Incertain embodiments, the first loading dose is about three times largerthan the maintenance dose, and the second loading dose is about twotimes larger than the maintenance dose.

The length of treatment with an NR or NAR derivative can be based on,e.g., the nature and severity of the disease/disorder or condition andthe response of the subject to the treatment. In certain embodiments, atherapeutically effective amount of an NR or NAR derivative isadministered over a period of about 1, 2, 3, 4, 5 or 6 days, or about 1,2, 3, 4, 5 or 6 weeks, to treat an acute disease/disorder or condition.Acute disorders and conditions include without limitation damage andinjury to tissues and organs (e.g., the brain, spinal cord, kidney andliver) and ischemic disorders (e.g., myocardial ischemia/infarction andcerebral ischemia/infarction). In other embodiments, a therapeuticallyeffective amount of an NR or NAR derivative is administered over aperiod of at least about 6 weeks, 8 weeks (2 months), 3 months, 6months, 1 year, 2 years, 3 years, 4 years, 5 years, 10 years or longerto treat a chronic disease/disorder or condition. It is understood thatthe delineation between acute and chronic may vary based on, e.g., theparticular disease/disorder or condition.

An NR or NAR derivative can also be taken pro re nata (as needed) untilclinical manifestations of the condition disappear or clinical targetsare achieved. For example, an NR or NAR derivative can be taken untilattainment of a target blood glucose level, blood pressure, blood levelsof lipids, body weight or body mass index, or any combination thereof.If clinical manifestations of the condition re-appear or the clinicaltargets are not maintained, administration of the NR or NAR derivativecan resume.

An NR or NAR derivative can be administered via any suitable route.Potential routes of administration of an NR or NAR derivative includewithout limitation oral, parenteral (including intradermal,subcutaneous, intravascular, intravenous, intra-arterial, intramuscular,intraperitoneal, intracavitary, intramedullary, intrathecal andtopical), and topical (including dermal/epicutaneous, transdermal,mucosal, transmucosal, intranasal [e.g., by nasal spray or drop],pulmonary [e.g., by oral or nasal inhalation], ocular [e.g., by eyedrop], buccal, sublingual, rectal [e.g., by suppository] and vaginal[e.g., by suppository]). In some embodiments, an NR or NAR derivative isadministered orally (e.g., as a tablet or capsule, optionally with anenteric coating). In other embodiments, an NR or NAR derivative isadministered parenterally (e.g., intravenously, subcutaneously orintramuscularly).

The mode of administration can depend on, e.g., the particulardisease/disorder or condition being treated. As an example, fortreatment of an ocular or retinal disorder, an NR or NAR derivative canbe administered, e.g., by eye drop. As another example, for treatment ofa skin disorder or condition, a topical composition containing an NR orNAR derivative can be applied to the affected area(s) of the skin. As anadditional example, for treatment of an airway disorder, an NR or NARderivative can be administered by oral inhalation.

An NR or NAR derivative can be administered at any time convenient tothe patient, such as in the morning or/and at nighttime (e.g., bedtime).Moreover, an NR or NAR derivative can be taken substantially with food(e.g., with a meal or within about 1 hour or 30 minutes before or aftera meal) or substantially without food (e.g., at least about 1 or 2 hoursbefore or after a meal).

The disclosure provides a method of treating a disease/disorder orcondition described herein, or bringing about a biological effectdescribed herein, comprising administering to a subject in need oftreatment a therapeutically effective amount of one or more NR/NARderivatives or a pharmaceutical composition comprising the same. Thedisclosure further provides one or more NR/NAR derivatives, or acomposition comprising one or more NR/NAR derivatives, for use as amedicament. In addition, the disclosure provides for the use of one ormore NR/NAR derivatives in the preparation of a medicament. Themedicament containing the one or more NR/NAR derivatives can be used totreat any disease/disorder or condition described herein or to bringabout any biological effect described herein. In certain embodiments,the one or more NR/NAR derivatives are or include a compound of FormulaII or IV. In further embodiments, the one or more NR/NAR derivatives areor include a compound of Formula I and a compound of Formula II, or acompound of Formula III and a compound of Formula IV. The one or moreNR/NAR derivatives can optionally be used with one or more additionaltherapeutic agents.

The description and all of the embodiments relating to therapeutic useof the NR and NAR derivatives described herein, including withoutlimitation the diseases/disorders and conditions that can be treated,the biological effects that can be achieved, the therapeuticallyeffective amount, loading dose/maintenance dose, the frequency and routeof administration, the length of treatment and combination therapies,also apply to therapeutic use of other NR and NAR derivatives (e.g.,NRTA, NRHTA, NARTA and NARHTA), and to therapeutic use of NR, NRH, NARand NARH, alone or in combination with one or more other therapeuticagents described herein (e.g., a PARP inhibitor).

Combination Therapies with Other Therapeutic Agents:

One or more NR/NAR derivatives disclosed herein can be used alone or incombination with one or more additional therapeutic agents to treat adisease/disorder or condition disclosed herein, or to bring about abiological effect disclosed herein. The additional therapeutic agent(s)can be administered prior to, concurrently with or subsequent toadministration of the NR/NAR derivative(s). Furthermore, the additionaltherapeutic agent(s) and the NR/NAR derivative(s) can be administered inthe same pharmaceutical composition or in separate compositions.

Other types of therapeutic agents that can be used in combination withthe NR and NAR derivatives of the disclosure include without limitationsirtuin-activating agents, AMPK-activating agents, CD38 inhibitors, PARPinhibitors, stimulators of cellular oxygen consumption, NMDA receptorantagonists, acetylcholinesterase inhibitors, antidiabetics,anti-obesity agents, antiplatelet agents, anticoagulants,antihypertensive agents, antioxidants, anti-inflammatory agents,analgesics, anesthetics, anticancer agents, antivirals, antibiotics,antifungals, natural compounds, vitamins and vaccines. The additionaltherapeutic agents can also include, e.g., farnesoid X receptor agonistsand sunblocks.

Combination therapies with PARP inhibitors are described in detail in aseparate section below. The disclosure in this section can also apply tocombination therapies with PARP inhibitors.

Sirtuin-activating agents include agents that increase the activity,level (e.g., expression) or signaling of a sirtuin such as SIRT1 orSIRT3. SIRT1 and SIRT3's beneficial properties are described above.Sirtuin-activating agents mimic calorie restriction, enhancemitochondrial and cellular function, enhance cell viability, increasecell lifespan, increase mitochondrial biogenesis, protect against fattyliver and muscle wasting, and have anti-inflammatory, antidiabetic,cardioprotective and anti-aging effects, among other therapeuticeffects. SIRT1-activating agents include without limitation lamin A,methylene blue, resveratrol, SRT-1460, SRT-1720, SRT-2104, SRT-2183, andanalogs, derivatives, fragments and salts thereof. In addition toresveratrol, other polyphenols that activate sirtuins such as SIRT1include, but are not limited to, butein, fisetin, isoliquiritigenin,piceatannol, quercetin, and analogs, derivatives and salts thereof.Metformin increases the activity of sirtuins such as SIRT1 by increasingNAD⁺ levels via activation of the NAD⁺ salvage pathway enzymenicotinamide phosphoribosyltransferase (NAMPT) and by increasing theNAD⁺/NADH ratio. Other sirtuin-activating agents include amino acidswith a branched side chain and metabolites thereof, including withoutlimitation leucine and its metabolites such as hydroxymethylbutyrate andketo-isocaproic acid/isocaproate. Such amino acids increase the levelsand stimulate the signaling of sirtuins such as SIRT1 and SIRT3.

AMPK-activating agents include agents that increase the activity, level(e.g., expression) or signaling of 5′-AMP-activated protein kinase(AMPK). AMPK plays an important role in cellular energy homeostasis,largely through stimulation of glucose and fatty acid uptake andoxidation when cellular energy is low. Activation of AMPK stimulateslipolysis, hepatic and skeletal muscle fatty acid oxidation, ketogenesisand glucose uptake, inhibits cholesterol and triglyceride synthesis andlipogenesis (including adipocyte lipogenesis), and modulates insulinsecretion by pancreatic β-cells. Activation of AMPK can also increaseNAD⁺ levels. AMPK-activating agents include without limitationsirtuin-activating agents (e.g., resveratrol, quercetin, metformin, andamino acids with a branched side chain and metabolites thereof),Lhiazolidinedione PPAR-γ agonists (infra, such as pioglitazone androsiglitazone), cannabinoids,5-aminoimidazole-4-caroxamide-1-β-D-riboside, berberine, curcumine,dinitrophenol (DNP), epigallocatechin-3-galate, α-lipoic acid, A-769662,PT-1, adiponectin, ghrelin, leptin, interleukin-6 (IL-6), and analogs,derivatives, fragments and salts thereof.

NAD⁺ and its precursor NMN are rapidly degraded by the extracellularglycohydrolase CD38. CD38 expression and activity increase during theaging process, which reduces NAD⁺ levels and leads to aging-relatedmetabolic dysfunction and disorders (e.g., inflammatory disorders).Inhibition of CD38 increases NAD⁺ levels and thereby improvesmitochondrial and cellular function and increases the activity ofsirtuins such as SIRT1 and SIRT3. CD38 inhibitors include, but are notlimited to, flavonoids (e.g., apigenin and quercetin),thiazoloquin(az)olin(on)es disclosed in C. Haffner et al., J. Med.Chem., 58:3548-3571 (2015) (e.g., compounds 76a, 76c, 77a, 77c, 77d,78a, 78c, 78d, 78e, 79a, 79c and 79d), and analogs, derivatives andsalts thereof.

Cellular oxygen consumption is a reliable indicator of mitochondrialactivity since mitochondrial activity is responsible for nearly alloxygen use by cells. Mitochondria play critical roles in variouscellular processes including energy production and biosynthesis. Agentsthat increase mitochondrial activity can be used, e.g., to treatmitochondrial diseases (e.g., Leigh syndrome and LHON),mitochondria-related diseases and conditions (e.g., metabolic disordersand neurodegenerative disorders [e.g., Alzheimer's disease, Parkinson'sdisease, ALS, Friedreich's ataxia and FXTAS]), to aid recovery frominjury (e.g., traumatic brain injury) or illness, and to delay aging.Stimulators of cellular oxygen consumption increase mitochondrialactivity through increased mitochondrial function or/and number.

Stimulators of cellular oxygen consumption include without limitationacarbose, chlormadinone (e.g., chlormadinone acetate), desoxymetasone,dichlorophene, enilconazole, flumazenil, quinidine (e.g., quinidinegluconate), succinylsulfathiazole, toltrazuril, and analogs, derivativesand salts thereof.

In some embodiments, one or more NR/NAR derivatives described herein areused in combination with an N-methyl-D-aspartate receptor (NMDAR)antagonist to treat a disorder characterized by neurodegeneration orneurotoxicity, such as a dementia (e.g., Alzheimer's disease) or a motorneuron disorder (e.g., Parkinson's disease). In certain embodiments, theNMDAR antagonist is an uncompetitive antagonist (or channel blocker)that has a moderate affinity (e.g., a K_(i) or IC₅₀ from about 200 nM toabout 10 μM) for the dizocilpine (MK-801)/phencyclidine-binding site ator near the Mg²⁺-binding site in the opened ion channel of activatedNMDAR, which allows the antagonist to inhibit NMDAR-mediatedexcitotoxicity while preserving physiological NMDAR activity. Such NMDARuncompetitive antagonists include without limitation alaproclate,amantadine, atomoxetine, budipine, delucemine, dextrallorphan,dextromethorphan, dextrorphan, dexanabinol, eliprodid ketamine,lanicemine, minocycline, memantine, nitromemantine, NEFA (a tricyclicsmall molecule), neramexane, orphenadrine, procyclidine, ARL/FPL12495/12495AA (desglycine metabolite of remacemide), and analogs,derivatives and salts thereof. In some embodiments, the NMDAR antagonistis memantine, nitromemantine, amantadine, lanicemine, neramexane,dextrall orphan, dextromethorphan, dextrorphan (metabolite ofdextromethorphan) or procyclidine. In certain embodiments, the NMDARantagonist is memantine, nitromemantine, dextrallorphan,dextromethorphan or dextrorphan.

In further embodiments, one or more NR/NAR derivatives disclosed hereinare used in combination with an acetylcholinesterase inhibitor (AChEI)to treat a cognitive disorder (e.g., a dementia such as Alzheimer'sdisease, Lewy body dementia or Parkinson-associated dementia) or aneuromuscular disorder (e.g., myasthenia gravis). Reversible AChEIsinclude, but are not limited to, neostigmine, physostigmine,pyridostigmine, rivastigmine, ambenonium, demecarium, donepezil,edrophonium, ladostigil, and analogs, derivatives and salts thereof.

Other therapeutic agents that can be used in conjunction with one ormore NR/NAR derivatives to treat Parkinson's disease include withoutlimitation levodopa, dopamine agonists (e.g., apomorphine,bromocriptine, cabergoline, lisuride, pergolide, piribedil, pramipexole,ropinirole and rotigotine), catechol-O-methyltransferase (COMT)inhibitors (e.g., entacapone, opicapone and tolcapone), monoamineoxidase B (MAO-B) inhibitors (e.g., ladostigil, safinamide, selegilineand rasagiline), peripheral aromatic L-amino acid decarboxylaseinhibitors (e.g., carbidopa), and analogs, derivatives and saltsthereof.

In additional embodiments, one or more NR/NAR derivatives disclosedherein are used in combination with one or more antidiabetic agents totreat hyperglycemia, insulin resistance or diabetes (e.g., type 1 ortype 2), or a disorder associated therewith (e.g., NAFLD or NASH). Incertain embodiments, the one or more antidiabetic agents are or includea biguanide (e.g., metformin), a thiazolidinedione (e.g., pioglitazoneor rosiglitazone), a GLP-1 agonist (e.g., dulaglutide or semaglutide) ora SGLT2 inhibitor (e.g., empagliflozin or tofogliflozin), or anycombination thereof.

Antidiabetic agents include without limitation:

-   -   AMP-activated protein kinase (AMPK) agonists, including        biguanides (e.g., buformin, metformin and phenformin);    -   peroxisome proliferator-activated receptor gamma (PPAR-γ)        agonists, including thiazolidinediones (e.g., balaglitazone,        ciglitazone, darglitazone, englitazone, lobeglitazone,        netoglitazone, pioglitazone, rivoglitazone, rosiglitazone and        troglitazone) and saroglitazar (dual PPAR-α/γ agonist);    -   glucagon-like peptide-1 (GLP-1) receptor agonists, including        exendin-4, albiglutide, dulaglutide, exenatide, liraglutide,        lixisenatide, semaglutide, taspoglutide, CNTO736, CNT03649,        HM11260C (LAPS-Exendin), NN9926 (OG9S7GT), TT401 and ZYOG1;    -   dual GLP-1 receptor (GLP-1R)/glucagon receptor (GCGR) agonists,        including longer-acting oxyntomodulin analogs {e.g.,        lipid-conjugated OXM analogs (e.g., DualAG disclosed in A. Pocai        et al., Diabetes, 58:2258-2266 [2009]), PEGylated OXM analogs,        cross-linked OXM analogs disclosed in A. Muppidi et al., ACS        Chem. Biol., 11:324-328 (2016) and OX-SR disclosed in R. Scott        et al., Peptides, 104:70-77 (2018)}, HM12525A, JNJ-54728518,        LY2944876 (TT-401), MED10382, MK-8521, MOD-6031, NN9277,        SAR425899, SP-1373 and ZP2929;    -   dual GLP-1R/gastric inhibitory peptide receptor (GIPR) agonists,        including Cpd86, LY3298176, NN9709 (MAR709), SAR438335, ZP-DI-70        and ZP-I-98;    -   triple GLP-1R/GIPR/GCGR agonists, including HM15211 and MAR423;    -   dipeptidyl peptidase 4 (DPP-4) inhibitors, including alogliptin,        anagliptin, dutogliptin, evogliptin, gemigliptin, gosogliptin,        linagliptin, omarigliptin, saxagliptin, septagliptin,        sitagliptin, des-fluoro-sitagliptin, teneligliptin, trelagliptin        and vildagliptin;    -   inhibitors of α-glucosidases, including acarbose, miglitol and        voglibose;    -   ketohexokinase (KHK) inhibitors, including PF-06835919;    -   sodium-glucose transport protein 2 (SGLT2) inhibitors, including        canagliflozin (also inhibits SGLT1), dapagliflozin,        empagliflozin, ertugliflozin, ipragliflozin, remogliflozin        etabonate, sotagliflozin (also inhibits SGLT1) and        tofogliflozin;    -   blockers of ATP-dependent K⁺ (K_(ATP)) channels on pancreatic        beta cells, including meglitinides (e.g., mitiglinide,        nateglinide and repaglinide) and sulfonylureas (including first        generation (e.g., acetohexamide, carbutamide, chlorpropamide,        glycyclamide [tolhexamide], metahexamide, tolazamide and        tolbutamide) and second generation (e.g., glibenclamide        [glyburide], glibornuride, gliclazide, glimepiride, glipizide,        gliquidone, glisoxepide and glyclopyramide)};    -   insulin and analogs thereof, including fast-acting insulin        (e.g., insulin aspart, insulin glulisine and insulin lispro),        intermediate-acting insulin (e.g., NPH insulin), and long-acting        insulin (e.g., insulin degiudec, insulin detemir and insulin        glargine); and    -   analogs, derivatives and salts thereof.

In further embodiments, one or more NR/NAR derivatives described hereinare used in combination with one or more anti-obesity agents to treatobesity or hyperlipidemia or a disorder associated therewith, such as ametabolic disorder (e.g., T2D, metabolic syndrome or NAFLD) or acardiovascular disorder (e.g., atherosclerosis or coronary arterydisease). Obesity also promotes inflammatory processes. In certainembodiments, the one or more anti-obesity agents are or include a lipaseinhibitor (e.g., orlistat) or/and an antihyperlipidemic agent (e.g., astatin such as atorvastatin, or/and a fibrate such as fenofibrate).

Anti-obesity agents include, but are not limited to:

-   -   appetite suppressants (anorectics), including amphetamine,        dexamphetamine, amfepramone, clobenzorex, mazindol, phentermine        (with or without topiramate) and lorcaserin;    -   pro-satiety agents, including ciliary neurotrophic factor (e.g.,        axokine) and longer-acting analogs of amylin, calcitonin,        cholecystokinin (CCK), glucagon (GCG), GLP-1, gastric inhibitory        peptide (GIP, also called glucose-dependent insulinotropic        polypeptide), leptin, oxyntomodulin (OXM), pancreatic        polypeptide (PP), peptide YY (PYY) and neuropeptide Y (NPY);    -   lipase inhibitors, including caulerpenyne, cetilistat,        ebelactone A and B, esterastin, lipstatin, orlistat,        percyquinin, panclicin A-E, valilactone and vibralactone;    -   agents that increase energy expenditure or/and fat burning,        including longer-acting glucagon analogs, glucagon receptor        agonists (e.g., NN9030) and dual GLP-1 receptor/glucagon        receptor agonists (supra); triiodothyronine (T₃) and thyroid        hormone receptor-beta (THR-β) agonists (e.g., MB07344, MB07811,        MGL-3196, MGL-3745, VK0214 and VK2809); and fibroblast growth        factor 21 (FGF21) and analogs and derivatives thereof (e.g.,        BMS-986036 [PEGylated FGF21]);    -   antihyperlipidemic agents;    -   other agents that reduce body weight or/and fat mass, including        dual GLP-1R/GIPR agonists (supra) and triple GLP-1R/GIPR/GCGR        agonists (supra); and    -   analogs, derivatives and salts thereof.

Antihyperlipidemic agents include without limitation:

-   -   HMG-CoA reductase inhibitors, including statins {e.g.,        atorvastatin, cerivastatin, fluvastatin, mevastatin, monacolins        (e.g., monacolin K [lovastatin]), pitavastatin, pravastatin,        rosuvastatin and simvastatin} and flavanones (e.g., naringenin);    -   squalene synthase inhibitors, including lapaquistat, zaragozic        acid and RPR-107393;    -   acetyl-CoA carboxylase (ACC) inhibitors, including anthocyanins,        avenaciolides, chloroacetylated biotin, cyclodim, diclofop,        haloxyfop, soraphens (e.g., soraphen A_(1α)),        5-(tetradecyloxy)-2-furancarboxylic acid (TOFA), CP-640186,        GS-0976, NDI-010976;        7-(4-propyloxy-phenylethynyl)-3,3-dimethyl-3,4        dihydro-2H-benzo[b][1,4]dioxepine;        N-ethyl-N′-(3-{[4-(3,3-dimethyl-1-oxo-2-oxa-7-azaspiro[4.5]dec-7-yl)piperidin-1-yl]-carbonyl}-1-benzothien-2-yl)urea;        5-(3-acetamidobut-1-ynyl)-2-(4-propyloxyphenoxy)thiazole; and        1-(3-{[4-(3,3-dimethyl-1-oxo-2-oxa-7-azaspiro[4.5]dec-7-yl)piperidin-1-yl]-carbonyl}-5-(pyridin-2-yl)-2-thienyl)-3-ethylurea;    -   ATP citrate lyase (ACL) inhibitors, including bempedoic acid        (ETC-1002), 2-furoic acid, (−)-hydroxycitric acid, BMS-303141,        MEDICA-16 and SB-204990;    -   PPAR-α agonists, including fibrates (e.g., bezafibrate,        ciprofibrate, clinofibrate, clofibric acid, clofibrate, aluminum        clofibrate [alfibrate], clofibride, etofibrate, fenofibric acid,        fenofibrate, gemfibrozil, ronifibrate and simfibrate),        isoflavones (e.g., daidzein and genistein), and        perfluoroalkanoic acids (e.g., perfluorooctanoic acid and        perfluorononanoic acid);    -   PPAR-δ agonists, including elafibranor (dual PPAR-α/δ agonist),        lanifibranor (triple PPAR-α/δ/γ agonist), GFT505 (dual PPAR-α/δ        agonist), GW0742, GW501516 (dual PPAR-β/δ agonist),        sodelglitazar (GW677954), MBX-8025, and isoflavones (e.g.,        daidzein and genistein);    -   PPAR-γ agonists, including thiazolidinediones (supra),        saroglitazar (dual PPAR-α/γ agonist), 4-oxo-2-thioxothiazolines        (e.g., rhodanine), berberine, honokiol, perfluorononanoic acid,        cyclopentenone prostaglandins (e.g., cyclopentenone        15-deoxy-Δ-prostaglandin J₂ [15d-PGJ₂]), and isoflavones (e.g.,        daidzein and genistein);    -   liver X receptor (LXR) agonists, including endogenous ligands        (e.g., oxysterols such as 22(R)-hydroxycholesterol,        24(S)-hydroxycholesterol, 27-hydroxycholesterol and cholestenoic        acid) and synthetic agonists (e.g., acetyl-podocarpic dimer,        hypocholamide, N,N-dimethyl-3β-hydroxy-cholenamide [DMHCA],        GW3965 and T0901317);    -   retinoid X receptor (RXR) agonists, including endogenous ligands        (e.g., 9-cis-retinoic acid) and synthetic agonists (e.g.,        bexarotene, AGN 191659, AGN 191701, AGN 192849, BMS649,        LG100268, LG100754 and LGD346);    -   triiodothyronine and thyroid hormone receptor-beta agonists        (supra);    -   ketohexokinase inhibitors (supra);    -   inhibitors of acyl-CoA cholesterol acyltransferase (ACAT, also        called sterol O-acyltransferase [SOAT], including ACAT1 [SOAT1]        and ACAT2 [SOAT2]), including avasimibe, pactimibe, pellitorine,        terpendole C and flavanones (e.g., naringenin);    -   inhibitors of stearoyl-CoA desaturase-1 (SCD-1, also called        stearoyl-CoA delta-9 desaturase) activity or expression,        including aramchol, CAY-10566, CVT-11127, SAR-224, SAR-707,        XEN-103;        3-(2-hydroxyethoxy)-4-methoxy-N-[5-(3-trifluoromethylbenzyl)thiazol-2-yl]benzamide        and        4-ethylamino-3-(2-hydroxyethoxy)-N-[5-(3-trifluoromethylbenzyl)thiazol-2-yl]benzamide;        1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4′-piperidine];        5-fluoro-1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,4′-piperidine];        6-[5-(cyclopropylmethyl)-4,5-dihydro-1′H,3H-spiro[1,5-benzoxazepine-2,4′-piperidin]-1′-yl]-N-(2-hydroxy-2-pyridin-3-ylethyl)pyridazine-3-carboxamide;        6-[4-(2-methylbenzoyl)piperidin-1-yl]pyridazine-3-carboxylic        acid (2-hydroxy-2-pyridin-3-ylethyl)amide;        4-(2-chlorophenoxy)-N-[3-(methyl        carbamoyl)phenyl]piperidine-1-carboxamide; the cis-9,trans-11        isomer and the trans-10,cis-12 isomer of conjugated linoleic        acid, substituted heteroaromatic compounds disclosed in WO        2009/129625 A1, anti-sense polynucleotides and peptide-nucleic        acids (PNAs) that target mRNA for SCD-1, and SCD-1-targeting        siRNAs;    -   cholesterylester transfer protein (CETP) inhibitors, including        anacetrapib, dalcetrapib, evacetrapib, torcetrapib and AMG 899        (TA-8995);    -   inhibitors of microsomal triglyceride transfer protein (MTTP)        activity or expression, including implitapide, lomitapide,        dirlotapide, mitratapide, CP-346086, JTT-130, SLx-4090,        anti-sense polynucleotides and PNAs that target mRNA for MTTP,        MTTP-targeting microRNAs (e.g., miRNA-30c), and MTTP-targeting        siRNAs;    -   GLP-1 receptor agonists (supra), glucagon receptor agonists        (supra) and dual GLP-1 receptor/glucagon receptor agonists        (supra);    -   fibroblast growth factor 21 (FGF21) and analogs and derivatives        thereof, including BMS-986036 (pegylated FGF21);    -   inhibitors of pro-protein convertase subtilisin/kexin type 9        (PCSK9) activity or expression, including berberine (reduces        PCSK9 level), annexin A2 (inhibits PCSK9 activity), anti-PCSK9        antibodies (e.g., alirocumab, bococizumab, evolocumab, LGT-209,        LY3015014 and RG7652), peptides that mimic the epidermal growth        factor-A (EGF-A) domain of the LDL receptor which binds to        PCSK9, PCSK9-binding adnectins (e.g., BMS-962476), anti-sense        polynucleotides and PNAs that target mRNA for PCSK9, and        IPCSK9-targeting siRNAs (e.g., inclisiran [ALN-PCS] and        ALN-PCS02);    -   FGF21 and analogs and derivatives thereof (supra);    -   apolipoprotein mimetic peptides, including apoA-I mimetics        (e.g., 2F, 3F, 3F-1, 3F-2, 3F-14, 4F, 4F-P-4F, 4F-IHS-4F, 4F2,        5F, 6F, 7F, 18F, 5A, 5A-C1, 5A-CH1, 5A-CH2, 5A-H1, 18A, 37 pA        [18A-P-18A], ELK [name], ELK-1A, ELK-1F, ELK-1K1A1E, ELK-1L1K,        ELK-1W, ELK-2A, ELK-2A2K2E, ELK-2E2K, ELK-2F, ELK-3E3EK,        ELK-3E3K3A, ELK-3E3LK, ELK-PA, ELK-P2A, ELKA [name], ELKA-CH2,        ATI-5261, CS-6253, ETC-642, FAMP [name], FREL [name] and KRES        [name]) and apoE mimetics (e.g., Ac-hE18A-NH₂ [AEM-28],        Ac-[R]hE18A-NH₂, AEM-28-14, EpK, hEp, mR18L, COG-112, COG-133        and COG-1410);    -   omega-3 fatty acids, including docosahexaenoic acid (DHA),        docosapentaenoic acid (DPA), eicosapentaenoic acid (EPA),        α-linolenic acid (ALA), fish oils (which contain, e.g., DHA and        EPA), and esters (e.g., glyceryl and ethyl esters) thereof; and    -   analogs, derivatives and salts thereof.

In other embodiments, one or more NR/NAR derivatives of the disclosureare used in combination with an antiplatelet agent or/and ananticoagulant to treat a thrombotic or hemostatic disorder, such as acardiovascular disorder (e.g., myocardial ischemia/infarction) or acerebrovascular disorder (e.g., ischemic stroke). In certainembodiments, the antiplatelet agent is or includes a COX-1 inhibitor(e.g., aspirin) or/and a P2Y₁₂ inhibitor (e.g., clopidogrel), and theanticoagulant is or includes a direct factor Xa inhibitor (e.g.,apixaban or rivaroxaban) or/and a direct thrombin inhibitor (e.g.,dabigatran).

Antiplatelet agents include without limitation:

-   -   cyclooxygenase (e.g., COX-1) inhibitors, including baspirin,        naproxen, triflusal and 2-hydroxy-4-trifluoromethylbenzoic acid        (the main metabolite of triflusal);    -   thromboxane (e.g., A₂) synthase inhibitors, including isbogrel,        ozagrel, picotamide, ridogrel, samixogrel, terbogrel and EV-077;    -   thromboxane (e.g., A₂) receptor antagonists, including        dipyridamole, ifetroban, isbogrel, picotamide, ramatroban,        ridogrel, samixogrel, terbogrel, terutroban, EV-077 and TRA-418;    -   adenosine diphosphate (ADP) receptor/P2Y₁₂ inhibitors, including        cangrelor, clopidogrel, prasugrel, ticagrelor and ticlopidine;    -   adenosine reuptake inhibitors, including cilostazol and        dipyridamole;    -   glycoprotein IIb/IIIa inhibitors, including abciximab,        eptifibatide, tirofiban, TRA-418, and prostacyclin and analogs        thereof;    -   phosphodiesterase (e.g., PDE3 or/and PDE5) inhibitors, including        cilostazol and dipyridamole;    -   protease-activated receptor 1 (PAR1) antagonists, including        vorapaxar;    -   prostacyclin and analogs thereof, including ataprost, beraprost        (e.g., esuberaprost),        5,6,7-trinor-4,8-inter-m-phenylene-9-fluoro-PGI₂, carbacyclin,        isocarbacyclin, clinprost (isocarbacyclin methyl ester),        ciprostene, eptaloprost, cicaprost (metabolite of eptaloprost),        iloprost, pimilprost, SM-10906 (des-methyl pimilprost),        naxaprostene, taprostene, treprostinil, CS-570, OP-2507 and        TY-11223; and    -   analogs, derivatives and salts thereof.

Anticoagulants include, but are not limited to:

-   -   vitamin K antagonists, including 4-hydroxycoumarins (e.g.,        acenocoumarol, brodifacoum, coumatetralyl, dicoumarol,        phenprocoumon, tioclomarol and warfarin) and 1,3-indandiones        (e.g., clorindione, diphenadione, fluindione and phenindione);    -   indirect factor Xa inhibitors, including heparin        (unfractionated), low molecular weight (MW) heparin (e.g.,        Fraxiparine®), low MW heparin derivatives (e.g., bemiparin,        certoparin, dalteparin, enoxaparin, nadroparin, parnaparin,        reviparin and tinzaparin), heparin analogs (e.g., fondaparinux        and idraparinux), and heparinoids (e.g., danaparoid, sulodexide        and dermatan sulfate);    -   direct factor Xa inhibitors, including apixaban, betrixaban,        darexaban, edoxaban, eribaxaban, letaxaban, otamixaban,        razaxaban, rivaroxaban, LY-517717 and YM-466;    -   direct thrombin (factor IIa) inhibitors (DTIs), including        univalent DTIs (e.g., argatroban, dabigatran, inogatran,        melagatran and ximelagatran) and bivalent DTIs (e.g., hirudin        and hirudin analogs [e.g., bivalirudin, desirudin and        lepirudin]); and    -   analogs, derivatives and salts thereof.

In additional embodiments, one or more NR/NAR derivatives disclosedherein are used in combination with one or more antihypertensive agents.Hypertension is a clinical feature of or is a major risk factor for awide range of disorders. Hypertension-associated disorders includewithout limitation cardiovascular disorders (e.g., cardiomyopathy, heartfailure, atherosclerosis, arteriosclerosis, coronary artery diseases[e.g., myocardial ischemia/infarction], and peripheral vascular diseases[e.g., peripheral artery disease]), cerebrovascular disorders (e.g.,stroke and cerebral infarction), metabolic disorders (e.g., metabolicsyndrome and T2D), kidney disorders (e.g., diabetic nephropathy,glomerulonephritis, renal ischemia, nephrotic syndrome, and kidneyfailure [e.g., acute kidney injury and chronic kidney disease]), liverfailure (e.g., cirrhosis), and eye disorders (e.g., retinopathy, damageto blood vessels in the eye, and vision loss).

Antihypertensive agents include without limitation:

-   -   antagonists of the renin-angiotensin-aldosterone system (RAAS),        including renin inhibitors (e.g., aliskiren),        angiotensin-converting enzyme (ACE) inhibitors (e.g.,        benazepril, captopril, enalapril, fosinopril, lisinopril,        moexipril, perindopril, quinapril, ramipril and trandolapril),        angiotensin II receptor type 1 (AT₁) antagonists (e.g.,        azilsartan, candesartan, eprosartan, fimasartan, irbesartan,        losartan, olmesartan medoxomil, olmesartan, telmisartan and        valsartan), and aldosterone receptor antagonists (e.g.,        eplerenone and spironolactone);    -   diuretics, including loop diuretics (e.g., bumetanide,        ethacrynic acid, furosemide and torsemide), thiazide diuretics        (e.g., bendroflumethiazide, chlorothiazide, hydrochlorothiazide,        epitizide, methyclothiazide and polythiazide), thiazide-like        diuretics (e.g., chlorthalidone, indapamide and metolazone),        cicletanine (an early distal tubular diuretic),        potassium-sparing diuretics (e.g., amiloride, eplerenone,        spironolactone and triamterene), and theobromine;    -   calcium channel blockers, including dihydropyridines (e.g.,        amlodipine, levamlodipine, cilnidipine, clevidipine, felodipine,        isradipine, lercanidipine, nicardipine, nifedipine, nimodipine,        nisoldipine and nitrendipine) and non-dihydropyridines (e.g.,        diltiazem and verapamil);    -   α₂-adrenoreceptor agonists, including clonidine, guanabenz,        guanfacine, methyldopa and moxonidine;    -   α₁-adrenoreceptor antagonists (alpha blockers), including        doxazosin, indoramin, nicergoline, phenoxybenzamine,        phentolamine, prazosin, terazosin and tolazoline;    -   β-adrenoreceptor (β₁ or/and β₂) antagonists (beta blockers),        including atenolol, betaxolol, bisoprolol, carteolol,        carvedilol, labetalol, metoprolol, nadolol, nebivolol,        oxprenolol, penbutolol, pindolol, propranolol and timolol;    -   mixed alpha/beta blockers, including bucindolol, carvedilol and        labetalol;    -   endothelin receptor antagonists, including selective ET_(A)        receptor antagonists (e.g., ambrisentan, atrasentan, edonentan,        sitaxentan, zibotentan and BQ-123) and dual ET_(A)/ET_(B)        antagonists (e.g., bosentan, macitentan and tezosentan);    -   other vasodilators, including hydralazine, minoxidil,        theobromine, sodium nitroprusside, organic nitrates (e.g.,        isosorbide mononitrate, isosorbide dinitrate and nitroglycerin,        which are converted to nitric oxide in the body), endothelial        nitric oxide synthase (eNOS) stimulators (e.g., cicletanine),        activators of soluble guanylate cyclase (e.g., cinaciguat and        riociguat), phosphodiesterase type 5 (PDE5) inhibitors (e.g.,        avanafil, benzamidenafil, dasantafil, dynafil, lodenafil,        mirodenafil, sildenafil, tadalafil, udenafil, vardenafil,        dipyridamole, papaverine, propentofylline, zaprinast and        T-1032), prostaglandin E₁ (alprostadil) and analogs thereof        (e.g., limaprost amd misoprostol), prostacyclin and analogs        thereof (supra), non-prostanoid prostacyclin receptor agonists        (e.g., 1-phthalazinol, ralinepag, selexipag, ACT-333679        [MRE-269, active metabolite of selexipag], and TRA-418),        phospholipase C (PLC) inhibitors, and protein kinase C (PKC)        inhibitors (e.g., BIM-1, BIM-2, BIM-3, BIM-8, chelerythrine,        cicletanine, gossypol, miyabenol C, myricitrin, ruboxistaurin        and verbascoside);    -   minerals, including magnesium and magnesium sulfate; and    -   analogs, derivatives and salts thereof.

In certain embodiments, the one or more antihypertensive agents are orinclude a thiazide or thiazide-like diuretic (e.g., hydrochlorothiazideor chlorthalidone), a calcium channel blocker (e.g., amlodipine ornifedipine), an ACE inhibitor (e.g., benazepril, captopril orperindopril) or an angiotensin II receptor antagonist (e.g., olmesartanmedoxomil, olmesartan, telmisartan or valsartan), or any combinationthereof.

In further embodiments, one or more NR/NAR derivatives described hereinare used in combination with one or more antioxidants to treat adisorder whose pathogenesis or pathophysiology involves oxidative stressor/and oxidative damage/injury. Such oxidative disorders include withoutlimitation neurodegenerative disorders (e.g., Alzheimer's, Huntington'sand Parkinson's diseases, ALS and multiple sclerosis), metabolicdisorders (e.g., types 1 and 2 diabetes and metabolic syndrome),cardiovascular disorders (e.g., atherosclerosis, heart failure,myocardial ischemia/infarction and IRI), cerebrovascular disorders(e.g., stroke and IRI), kidney disorders (e.g., diabetic nephropathy),liver disorders (e.g., cirrhosis), and eye disorders (e.g., AMD).Furthermore, oxidants (e.g., ROS) and oxidized molecules (e.g., oxidizedlipids) can be highly inflammatory.

Antioxidants include without limitation:

-   -   vitamins and analogs thereof, including vitamin A, vitamin B₃        (e.g., niacin [nicotinic acid] and nicotinamide), vitamin C        (ascorbic acid), vitamin E (including tocopherols [e.g.,        α-tocopherol] and tocotrienols), and vitamin E analogs (e.g.,        trolox [water-soluble]);    -   carotenoids, including carotenes (e.g., β-carotene),        xanthophylls (e.g., lutein, zeaxanthin and meso-zeaxanthin), and        carotenoids in saffron (e.g., crocin and crocetin);    -   sulfur-containing antioxidants, including glutathione (GSH),        N-acetyl-L-cysteine (NAC), bucillamine,        S-nitroso-N-acetyl-L-cysteine (SNAC), S-allyl-L-cysteine (SAC),        S-adenosyl-L-methionine (SAM), α-lipoic acid and taurine;    -   scavengers of ROS and radicals, including carnosine,        N-acetylcarnosine, curcuminoids (e.g., curcumin,        demethoxycurcumin and tetrahydrocurcumin), cysteamine, ebselen,        glutathione, hydroxycinnamic acids and derivatives (e.g., esters        and amides) thereof (e.g., caffeic acid, rosmarinic acid and        tranilast), melatonin and metabolites thereof, nitrones (e.g.,        disufenton sodium [NXY-059]), nitroxides (e.g., XJB-5-131),        polyphenols (e.g., flavonoids [e.g., apigenin, genistein,        luteolin, naringenin and quercetin]), superoxide dismutase        mimetics (infra), tirilazad, vitamin C, vitamin E and analogs        thereof (e.g., α-tocopherol and trolox), and xanthine        derivatives (e.g., pentoxifylline);    -   inhibitors of enzymes that produce ROS, including NADPH oxidase        (NOX) inhibitors (e.g., apocynin, decursin and decursinol        angelate [both inhibit NOX-1, -2 and -4 activity and        expression], diphenylene iodonium, and GKT-831 [formerly        GKT-137831, a dual NOX1/4 inhibitor]), NADH:ubiquinone        oxidoreductase (complex I) inhibitors (e.g., metformin and        rotenone), and myeloperoxidase inhibitors (e.g., azide and        4-aminobenzoic acid hydrazide, and apoE mimetics such as AEM-28        and AEM-28-14);    -   substances that mimic or increase the activity or production of        antioxidant enzymes, including superoxide dismutase (SOD) {e.g.,        SOD mimetics such as manganese (III)- and zinc (III)-porphyrin        complexes (e.g., MnTBAP, MnTMPyP and ZnTBAP), manganese (II)        penta-azamacrocyclic complexes (e.g., M40401 and M40403),        manganese (III)-salen complexes (e.g., those disclosed in U.S.        Pat. No. 7,122,537) and OT-551 (a cyclopropyl ester prodrug of        tempol hydroxylamine), and resveratrol and apoA-I mimetics such        as 4F (both increase expression)}, catalase (e.g., catalase        mimetics such as manganese (III)-salen complexes [e.g., those        disclosed in U.S. Pat. No. 7,122,537], and zinc [increases        activity]), glutathione peroxidase (GPx) (e.g., apomorphine and        zinc [both increase activity], and beta-catenin, etoposide and        resveratrol [all three increase expression]), glutathione        reductase (e.g., 4-tert-butylcatechol and redox cofactors such        as flavin adenine dinucleotide [FAD] and NADPH [all three        enhance activity]), glutathione S-transferase (GST) (e.g.,        phenylalkyl isothiocyanate-cysteine conjugates {e.g.,        S—[N-benzyl(thiocarbamoyl)]-L-cysteine}, phenobarbital, rosemary        extract and carnosol [all enhance activity]), thioredoxin (Trx)        (e.g., geranylgeranylacetone, prostaglandin E_(i) and        sulforaphane [all increase expression]), NADPH-quinone        oxidoreductase 1 (NQO1) {e.g., flavones [e.g., β-naphthoflavone        (5,6-benzoflavone)] and triterpenoids [e.g., oleanolic acid        analogs such as TP-151 (CDDO), TP-155 (CDDO methyl ester),        TP-190, TP-218, TP-222, TP-223 (CDDO carboxamide), TP-224 (CDDO        monomethylamide), TP-225, TP-226 (CDDO dimethylamide), TP-230,        TP-235 (CDDO imidazolide), TP-241, CDDO monoethylamide, CDDO        mono(trifluoroethyl)amide, and (+)-TBE-B], all of which increase        expression by activating Nrf2}, heme oxygenase 1 (HO-1) {e.g.,        curcuminoids (e.g., curcumin), triterpenoids (e.g., oleanolic        acid analogs [supra, such as TP-225]), and apoA-I mimetics        (supra, such as 4F), all of which increase expression}, and        paraoxonase 1 (PON-1) (e.g., apoE mimetics [supra, such as        AEM-28 and AEM-28-14] and apoA-I mimetics [supra, such as 4F],        both types increasing activity);    -   activators of transcription factors that upregulate expression        of antioxidant enzymes, including activators of nuclear factor        (erythroid-derived 2)-like 2 (NFE2L2 or Nrf2) {e.g., bardoxolone        methyl, OT-551, fumarates (e.g., dimethyl and monomethyl        fumarate), dithiolethiones (e.g., oltipraz), flavones (e.g.,        p-naphthoflavone), isoflavones (e.g., genistein), sulforaphane,        trichostatin A, triterpenoids (e.g., oleanolic acid analogs        [supra, such as TP-225]), and melatonin (increases Nrf2        expression)};    -   mitochondria-targeted antioxidants, including MitoE and MitoQ;    -   other kinds of antioxidants, including anthocyanins, benzenediol        abietane diterpenes (e.g., carnosic acid), cyclopentenone        prostaglandins (e.g., 15d-PGJ₂), flavonoids {e.g., flavonoids in        Ginkgo biloba (e.g., myricetin and quercetin [increases levels        of GSH, SOD, catalase, GPx and GST]), prenylflavonoids (e.g.,        isoxanthohumol), flavones (e.g., apigenin), isoflavones (e.g.,        genistein), flavanones (e.g., naringenin) and flavanols (e.g.,        catechin and epigallocatechin-3-gallate)}, omega-3 fatty acids        and esters thereof (supra), phenylethanoids (e.g., tyrosol and        hydroxytyrosol), retinoids (e.g., all-trans retinol [vitamin        A]), stilbenoids (e.g., resveratrol), uric acid, apoA-I mimetics        (e.g., 4F), apoE mimetics (e.g., AEM-28 and AEM-28-14), and        minerals (e.g., selenium and zinc [e.g., zinc monocysteine]);        and    -   analogs, derivatives and salts thereof.

In certain embodiments, the one or more antioxidants are or include avitamin or an analog thereof (e.g., vitamin E or an analog thereof suchas α-tocopherol or trolox) or/and an ROS or radical scavenger (e.g.,melatonin or/and glutathione). In other embodiments, the antioxidantor/and the natural compound are selected from resveratrol,pterostilbene, ellagic acid, urolithin A, quercetin, coenzyme Q,glutathione, N-acetyl-L-cysteine, α-lipoic acid, melatonin, creatine,S-adenosyl methionine, leucine, pyruvic acid/pyruvate and combinationsthereof.

In some embodiments, one or more NR/NAR derivatives are used inconjunction with one or more B vitamins selected from thiamine (B₁),riboflavin (B₂), niacin (B₃), pantothenic acid (B₅), pyridoxine (B₆),biotin (B₇), folic acid (B₉) and cobalamin (B₁₂). In certainembodiments, one or more NR/NAR derivatives are used in conjunction withvitamin B₁, B₂, B₃ or B₆, or any combination thereof.

In additional embodiments, one or more NR/NAR derivatives disclosedherein are used in combination with one or more anti-inflammatory agentsto treat an inflammatory disorder. Inflammation contributes to thepathogenesis or pathophysiology of a wide range of disorders.Furthermore, inflammation is a major stimulant of fibrosis. In certainembodiments, the one or more anti-inflammatory agents are or include andNSAID or/and an inhibitor of a pro-inflammatory cytokine or a receptortherefor or the production thereof (e.g., TNF-α, IL-4, IL-6 or IL-23, orany combination thereof).

Anti-inflammatory agents include without limitation:

-   -   non-steroidal anti-inflammatory drugs (NSAIDs), including those        listed below;    -   immunomodulators, including imides (e.g., thalidomide,        lenalidomide, pomalidomide and apremilast) and xanthine        derivatives (e.g., lisofylline, pentoxifylline and        propentofylline);    -   immunosuppressants, including interferon-beta (IFN-β)        glucocorticoids (infra), antimetabolites (e.g., hydroxyurea        [hydroxycarbamide], antifolates [e.g., methotrexate], and purine        analogs [e.g., azathioprine, mercaptopurine and thioguanine]),        pyrimidine synthesis inhibitors (e.g., leflunomide and        teriflunomide), calcineurin inhibitors (e.g., ciclosporin        [cyclosporine A], pimecrolimus and tacrolimus),        inosine-5′-monophosphate dehydrogenase (IMPDH) inhibitors (e.g.,        mycophenolic acid and derivatives thereof [e.g., mycophenolate        sodium and mycophenolate mofetil]), mechanistic/mammalian target        of rapamycin (mTOR) inhibitors (e.g., rapamycin [sirolimus],        deforolimus [ridaforolimus], everolimus, temsirolimus,        umirolimus [biolimus A9], zotarolimus and RTP-801), modulators        of sphingosine-1-phosphate receptors (e.g., S1PR1) (e.g.,        fingolimod), and serine C-palmitoyltransferase inhibitors (e.g.,        myriocin);    -   anti-inflammatory cytokines and compounds that increase their        production, including IL-10 and compounds that increase IL-10        production {e.g., S-adenosyl-L-methionine, melatonin, metformin,        rotenone, curcuminoids (e.g., curcumin), prostacyclin and        analogs thereof (supra) triterpenoids (e.g., oleanolic acid        analogs [supra, such as TP-225]), and apoA-I mimetics (supra,        such as 4F)};    -   inhibitors of pro-inflammatory cytokines or receptors therefor,        including inhibitors of (e.g., antibodies or fragments thereof        targeting) tumor necrosis factor-alpha (TNF-α) (e.g.,        adalimumab, certolizumab pegol, golimumab, infliximab,        etanercept, bupropion, curcumin, catechins and ART-621) or the        receptor therefor (TNFR1), inhibitors of thymic stromal        lymphopoietin (e.g., anti-TSLP antibodies and fragments thereof        [e.g., tezepelumab and M702] and immunoconjugates comprising the        extracellular domain of TSLPR) or the receptor therefor (TSLPR),        inhibitors of (e.g., antibodies or fragments thereof targeting)        pro-inflammatory interferons (e.g., interferon-alpha [IFN-α]) or        receptors therefor, inhibitors of (e.g., antibodies or fragments        thereof targeting) pro-inflammatory interleukins or receptors        therefor {e.g., IL-1 (e.g., IL-1α and IL-1β [e.g., canakinumab        and rilonacept]) or IL-1R (e.g., anakinra and isunakinra        [EBI-005]), IL-2 or IL-2R (e.g., basiliximab and daclizumab),        IL-4 or IL-4R (e.g., dupilumab), IL-5 (e.g., mepolizumab and        reslizumab) or IL-5R, IL-6 (e.g., clazakizumab, elsilimomab,        olokizumab, siltuximab and sirukumab) or IL-6R (e.g., sarilumab        and tocilizumab), IL-8 or IL-8R, IL-12 (e.g., briakinumab and        ustekinumab) or IL-12R, IL-13 or IL-13R, IL-15 or IL-15R, IL-17        (e.g., ixekizumab and secukinumab) or IL-17R (e.g., brodalumab),        IL-18 (e.g., GSK1070806) or IL-18R, IL-20 (e.g., the antibody        7E) or IL-20R, IL-22 (e.g., fezakinumab) or IL-22R, IL-23 (e.g.,        briakinumab, guselkumab, risankizumab, tildrakizumab        [SCH-900222], ustekinumab and BI-655066) or IL-23R, IL-31 (e.g.,        anti-IL-31 antibodies disclosed in U.S. Pat. No. 9,822,177) or        IL-31R (e.g., anti-IL-31 receptor A antibodies such as        nemolizumab), IL-33 or IL-33R, and IL-36 or IL-36R}, and        inhibitors of monocyte chemoattractant protein 1 (MCP-1) {e.g.,        bindarit, anti-MCP1 antibodies (e.g., 5D3-F7 and 10F7),        MCP1-binding peptides (e.g., HSWRHFHTLGGG), and MCP1-binding RNA        aptamers (e.g., ADR22 and mNOX-E36 [a spiegelmer])} or receptors        therefor (e.g., CCR2 antagonists such as spiropiperidines [e.g.,        RS-29634, RS-102895 and RS-504393]);    -   inhibitors of the production of pro-inflammatory cytokines or        receptors therefor, including inhibitors of the production of        TNF-α {e.g., N-acetyl-L-cysteine, S-adenosyl-L-methionine,        L-carnitine, hydroxychloroquine, melatonin, parthenolide,        pirfenidone, sulfasalazine, mesalazine (5-aminosalicylic acid),        taurine, flavonoids (e.g., epigallocatechin-3-gallate [EGCG],        naringenin and quercetin), omega-3 fatty acids and esters        thereof, glucocorticoids, immunomodulatory imides and xanthine        derivatives, PDE4 inhibitors, serine protease inhibitors (e.g.,        gabexate and nafamostat), prostacyclin and analogs thereof,        SOCS1 mimetics (infra), myxoma virus M013 protein, Yersinia YopM        protein, apoA-I mimetics (e.g., 4F), and apoE mimetics (e.g.,        AEM-28 and hEp)}, IFN-α (e.g., alefacept), IL-1 (e.g., IL-1α and        IL-1β)(e.g., chloroquine, hydroxychloroquine, nafamostat,        pirfenidone, sulfasalazine, mesalazine, prostacyclin and analogs        thereof, glucocorticoids, TNF-α inhibitors, PAR1 antagonists        [e.g., vorapaxar], M013 protein, YopM protein and apoA-I        mimetics [e.g., 4F]), IL-1β (e.g. melatonin, metformin,        rotenone, flavonoids [e.g., EGCG and naringenin], annexin A1        mimetics, and caspase-1 inhibitors [e.g., belnacasan,        pralnacasan and parthenolide]), IL-2 (e.g., glucocorticoids,        calcineurin inhibitors and PDE4 inhibitors), IL-4 (e.g.,        glucocorticoids and serine protease inhibitors [e.g., gabexate        and nafamostat]), IL-5 (e.g., glucocorticoids), IL-6 (e.g.,        nafamostat, parthenolide, prostacyclin and analogs thereof,        tranilast, L-carnitine, taurine, flavonoids [e.g., EGCG,        naringenin and quercetin], omega-3 fatty acids and esters        thereof, glucocorticoids, immunomodulatory imides, TNF-α        inhibitors, M013 protein and apoE mimetics [e.g., AEM-28 and        hEp]), IL-8 (e.g., alefacept and glucocorticoids), IL-12 (e.g.,        apilimod, PDE4 inhibitors and YopM protein), IL-15 (e.g., YopM        protein), IL-17 (e.g., protein kinase C inhibitors such as        sotrastaurin), IL-18 (e.g., M013 protein, YopM protein and        caspase-1 inhibitors), and IL-23 (e.g., apilimod, alefacept and        PDE4 inhibitors), and MCP-1 (e.g., EGCG, melatonin and        tranilast);    -   inhibitors of pro-inflammatory transcription factors or their        activation or expression, including inhibitors of NF-κB or its        activation or expression {e.g., aliskiren, melatonin,        minocycline and parthenolide (both inhibit NF-κB nuclear        translocation), nafamostat, niclosamide, (−)-DIMEQ, IT-603,        IT-901, PBS-1086, flavonoids (e.g., EGCG and quercetin),        hydroxycinnamic acids and esters thereof (e.g., ethyl caffeate),        lipoxins (e.g., 15-epi-LXA4 and LXB4), omega-3 fatty acids and        esters thereof, stilbenoids (e.g., resveratrol), statins (e.g.,        rosuvastatin), triterpenoids (e.g., oleanolic acid analogs such        as TP-225), TNF-α inhibitors, apoE mimetics (e.g., AEM-28), M013        protein, penetratin, and activators of sirtuin 1 (SIRT1, which        inhibits NF-κB) (e.g., flavones [e.g., luteolin],        phenylethanoids [e.g., tyrosol, which induces SIRT1 expression],        stilbenoids [e.g., resveratrol, which increases SIRT1 activity        and expression] and lamin A)}, and inhibitors of STAT (signal        transducer and activator of transcription) proteins or their        activation or expression {e.g., Janus kinase 1 (JAK1) inhibitors        (e.g., itacitinib, upadacitinib, GLPG0634 and GSK2586184), JAK2        inhibitors (e.g., lestaurtinib, pacritinib, CYT387, TG101348,        SOCS1 mimetics and SOCS3 mimnetics), JAK3 inhibitors (e.g.,        ASP-015K, R348 and VX-509), dual JAK1/JAK2 inhibitors (e.g.,        baricitinib and ruxolitinib), dual JAK1/JAK3 inhibitors (e.g.,        tofacitinib), suppressor of cytokine signaling (SOCS) mimetic        peptides (e.g., SOCS1 mimetics [e.g., SOCS1-KIR, NewSOCS1-KIR,        PS-5 and Tkip] and SOCS3 mimetics), niclosamide, hydroxycinnamic        acids and esters thereof (e.g., rosmarinic acid), and lipoxins        (e.g., 15-epi-LXA4 and LXB4)}; inhibitors of pro-inflammatory        prostaglandins (e.g., prostaglandin E₂ [PGE₂]) or    -   receptors therefor (e.g., EP₃) or the production thereof,        including cyclooxygenase inhibitors (e.g., NSAIDs [including        non-selective COX-1/COX-2 inhibitors such as aspirin and        selective COX-2 inhibitors such as coxibs], glucocorticoids        [which inhibit COX activity and expression], omega-3 fatty acids        and esters thereof, curcuminoids [e.g., curcumin], stilbenoids        [e.g., resveratrol, which inhibits COX-1 and -2 activity and        expression], and vitamin E and analogs thereof [e.g.,        α-tocopherol and trolox]), cyclopentenone prostaglandins (e.g.,        prostaglandin J₂ [PGJ₂], Δ12-PGJ₂ and 15-deoxy-Δ12,14-PGJ₂),        hydroxycinnamic acids and esters thereof (e.g., ethyl caffeate,        which suppresses COX-2 expression), and triterpenoids (e.g.,        oleanolic acid analogs such as TP-225, which suppress COX-2        expression);    -   inhibitors of leukotrienes or receptors therefor or the        production thereof, including cysteinyl leukotriene receptor 1        (cysLTR1) antagonists (e.g., cinalukast, gemilukast [dual        cysLTR1/cysLTR2 antagonist], iralukast, montelukast, pranlukast,        tomelukast, verlukast, zafirlukast, CP-195494, CP-199330,        ICI-198615, MK-571 and lipoxins [e.g., LXA4 and 15-epi-LXA4]),        cysLTR2 antagonists (e.g., HAMI-3379), 5-lipoxygenase (5-LOX)        inhibitors (e.g., baicalein, caffeic acid, curcumin, hyperforin,        γ-linolenic acid [GLA], meclofenamic acid, meclofenamate sodium,        minocycline, zileuton, MK-886, and omega-3 fatty acids and        esters thereof), and immunomodulatory xanthine derivatives;    -   inhibitors of phospholipase A2 (e.g., secreted and cytosolic        PLA2), including glucocorticoids, arachidonyl trifluoromethyl        ketone, bromoenol lactone, chloroquine, cytidine        5-diphosphoamines, darapladib, quinacrine, vitamin E, RO-061606,        ZPL-521, lipocortins (annexins, such as annexin A1), and annexin        mimetic peptides (e.g., annexin A1 mimetics [e.g., Ac2-26 and        CGEN-855A]);    -   suppressors of C-reactive protein (CRP) activity or level,        including statins (e.g., rosuvastatin), thiazolidinediones        (supra), DPP-4 inhibitors (supra), stilbenoids (e.g.,        resveratrol), epigallocatechin-3-gallate and CRP-i2;    -   mast cell stabilizers, including cromoglicic acid (cromolyn),        ketotifen, methylxanthines, nedocromil, nicotinamide,        olopatadine, omalizumab, pemirolast, quercetin and zinc sulfate;    -   phosphodiesterase inhibitors, including PDE4 inhibitors (e.g.,        apremilast, cilomilast, ibudilast, piclamilast, roflumilast,        crisaborole, diazepam, luteolin, mesembrenone, rolipram, AN2728        and E6005);    -   specialized pro-resolving mediators (SPMs), including        metabolites of polyunsaturated fatty acids (PUFAs) such as        lipoxins (e.g., LXA4, 15-epi-LXA4, LXB4 and 15-epi-LXB4),        resolvins (e.g., resolvins derived from        5Z,8Z,11Z,14Z,17Z-eicosapentaenoic acid [EPA], resolvins derived        from 4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid [DHA], and        resolvins derived from 7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid        [n-3 DPA]), protectins/neuroprotectins (e.g., DHA-derived        protectins/neuroprotectins and n-3 DPA-derived        protectins/neuroprotectins), maresins (e.g., DHA-derived        maresins and n-3 DPA-derived maresins), n-3 DPA metabolites, n-6        DPA (4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid) metabolites,        oxo-DHA metabolites, oxo-DPA metabolites, docosahexaenoyl        ethanolamide metabolites, cyclopentenone prostaglandins (e.g.,        Δ12-PGJ₂ and 15-deoxy-Δ12,14-PGJ₂), and cyclopentenone        isoprostanes (e.g., 5,6-epoxyisoprostane Δ₂ and        5,6-epoxyisoprostane E₂);    -   other kinds of anti-inflammatory agents, including pirfenidone,        nintedanib, vitamin A, omega-3 fatty acids and esters thereof,        apoA-I mimetics (e.g., 4F), apoE mimetics (e.g., AEM-28 and        AEM-28-14), and antioxidants (e.g., sulfur-containing        antioxidants); and    -   analogs, derivatives, fragments and salts thereof.

Non-steroidal anti-inflammatory drugs (NSAIDs) include withoutlimitation:

-   -   acetic acid derivatives, such as aceclofenac, bromfenac,        diclofenac, etodolac, indomethacin, ketorolac, nabumetone,        sulindac, sulindac sulfide, sulindac sulfone and tolmetin;    -   anthranilic acid derivatives (fenamates), such as flufenamic        acid, meclofenamic acid, mefenamic acid and tolfenamic acid;    -   enolic acid derivatives (oxicams), such as droxicam, isoxicam,        lornoxicam, meloxicam, piroxicam and tenoxicam;    -   propionic acid derivatives, such as fenoprofen, flurbiprofen,        ibuprofen, dexibuprofen, ketoprofen, dexketoprofen, loxoprofen,        naproxen and oxaprozin;    -   salicylates, such as diflunisal, salicylic acid, acetylsalicylic        acid (aspirin), choline magnesium trisalicylate, salsalate and        mesalazine;    -   COX-2-selective inhibitors, such as apricoxib, celecoxib,        etoricoxib, firocoxib, fluorocoxibs (e.g., fluorocoxibs A-C),        lumiracoxib, mavacoxib, parecoxib, rofecoxib, tilmacoxib        (JTE-522), valdecoxib, 4-O-methylhonokiol, niflumic acid,        DuP-697, CG100649, GW406381, NS-398, SC-236, SC-58125,        benzothieno[3,2-d]pyrimidin-4-one sulfonamide thio-derivatives,        and COX-2 inhibitors derived from Tribulus terrestris;    -   other kinds of NSAIDs, such as monoterpenoids (e.g., eucalyptol        and phenols [e.g., carvacrol]), anilinopyridinecarboxylic acids        (e.g., clonixin), sulfonanilides (e.g., nimesulide), and dual        inhibitors of lipooxygenase (e.g., 5-LOX) and cyclooxygenase        (e.g., COX-2) {e.g., chebulagic acid, licofelone,        2-(3,4,5-trimethoxyphenyl)-4-(N-methylindol-3-yl)thiophene, and        di-tert-butylphenol-based compounds (e.g., DTPBHZ, DTPINH,        DTPNHZ and DTPSAL)}; and    -   analogs, derivatives and salts thereof.

The glucocorticoid class of corticosteroids has anti-inflammatory andimmunosuppressive properties. Glucocorticoids include without limitationhydrocortisone types (e.g., cortisone and derivatives thereof [e.g.,cortisone acetate], hydrocortisone and derivatives thereof [e.g.,hydrocortisone acetate, hydrocortisone-17-aceponate,hydrocortisone-17-buteprate, hydrocortisone-17-butyrate andhydrocortisone-17-valerate], prednisolone, methylprednisolone andderivatives thereof [e.g., methylprednisolone aceponate], prednisone,and tixocortol and derivatives thereof [e.g., tixocortol pivalate]),betamethasone types (e.g., betamethasone and derivatives thereof [e.g.,betamethasone dipropionate, betamethasone sodium phosphate andbetamethasone valerate], dexamethasone and derivatives thereof [e.g.,dexamethasone sodium phosphate], and fluocortolone and derivativesthereof [e.g., fluocortolone caproate and fluocortolone pivalate]),halogenated steroids (e.g., alclometasone and derivatives thereof [e.g.,alclometasone dipropionate], beclometasone and derivatives thereof[e.g., beclometasone dipropionate], clobetasol and derivatives thereof[e.g., clobetasol-17-propionate], clobetasone and derivatives thereof[e.g., clobetasone-17-butyrate], desoximetasone and derivatives thereof[e.g., desoximetasone acetate], diflorasone and derivatives thereof[e.g., diflorasone diacetate], diflucortolone and derivatives thereof[e.g., diflucortolone valerate], fluprednidene and derivatives thereof[e.g., fluprednidene acetate], fluticasone and derivatives thereof[e.g., fluticasone propionate], halobetasol [ulobetasol] and derivativesthereof [e.g., halobetasol proprionate], halometasone and derivativesthereof [e.g., halometasone acetate], and mometasone and derivativesthereof [e.g., mometasone furoate]), acetonides and related substances(e.g., amcinonide, budesonide, ciclesonide, desonide, fluocinonide,fluocinolone acetonide, flurandrenolide [flurandrenolone orfludroxycortide], halcinonide, triamcinolone acetonide and triamcinolonealcohol), carbonates (e.g., prednicarbate), and analogs, derivatives andsalts thereof.

In additional embodiments, one or more NR/NAR derivatives of thedisclosure are used in conjunction with one or more antifibrotic agentsto treat a fibrotic disorder. In some embodiments, the one or moreantifibrotic agents are or include an anti-inflammatory agent or/and anantioxidant (e.g., vitamin E or an analog thereof [e.g., α-tocopherol ortrolox], a sulfur-containing antioxidant or an ROS or radical scavenger[e.g., melatonin], or any combination thereof). In certain embodiments,the one or more antifibrotic agents are or include pirfenidone (whichamong its various antifibrotic and anti-inflammatory propertiesdescribed herein also reduces fibroblast proliferation) or/andnintedanib (which blocks signaling of fibroblast growth factor receptors[FGFRs], platelet-derived growth factor receptors [PDGFRs] and vascularendothelial growth factor receptors [VEGFRs] involved in fibroblastproliferation, migration and transformation).

In further embodiments, the one or more antifibrotic agents are orinclude one or more agents that have anti-hyperglycemic or/andinsulin-sensitizing activity for treatment of a fibrotic disorder inwhich hyperglycemia, diabetes or insulin resistance contributes todevelopment of fibrosis. Examples of such a disorder include diabeticnephropathy, which is characterized by renal fibrosis, and NASH andcirrhosis, both of which are characterized by hepatic fibrosis. Use ofanti-hyperglycemic or/and insulin-sensitizing agent(s) can curtail orprevent, e.g., renal inflammation and fibrosis or hepatic inflammationand fibrosis. In certain embodiments, the one or more antifibroticagents are or include a PPAR-γ agonist (e.g., a thiazolidinedione[supra], such as pioglitazone or rosiglitazone). PPARγ-activatingthiazolidinediones have both anti-hyperglycemic and insulin-sensitizingproperties.

Antifibrotic agents include without limitation:

-   -   inhibitors of collagen accumulation, including protein kinase C        (PKC) inhibitors (supra, inhibit collagen production),        colchicine and its metabolite colchiceine (both inhibit collagen        synthesis and deposition), dilinoleoyl-phosphatidylcholine        (inhibits collagen production induced by transforming growth        factor-beta1 [TGF-β1]), luteolin (reduces fibrosis in part by        increasing expression of matrix metalloproteinase 9 [MMP-9] and        metallothionein, which degrade the extracellular matrix [ECM]),        malotilate (reduces procollagen I α2 [Col1a2] expression),        melatonin (inhibits expression of procollagens I and III),        S-nitroso-N-acetyl-L-cysteine (reduces collagen I amount in part        by activating MMP-13 and suppressing tissue inhibitor of        metalloproteinases 2 [TIMP-2]), oxymatrine {reduces procollagen        I α1 (Col1a1) (and α-smooth muscle actin [α-SMA]) expression},        pioglitazone (reduces collagen I [and α-SMA] production),        pirfenidone (reduces production of procollagens I and II and        inhibits TGF-β-stimulated collagen production), quercetin        (reduces Col1a1 and procollagen III α1 [Col3a1] expression),        resveratrol (reduces collagen I [and α-SMA] production), RGD        mimetics and analogs (infra, reduce collagen I accumulation in        part by increasing secretion of collagenases), safironil        (reduces collagen I [and α-SMA] production), statins (e.g.,        atorvastatin, lovastatin and simvastatin [all three reduce        collagen production]), tranilast (inhibits procollagen        expression and fibroblast proliferation), valproic acid (reduces        collagen deposition), inhibitors of collagen cross-linking        {e.g., D-penicillamine and lysyl oxidase-like 2 (LOXL2, which        promotes collagen cross-linking) inhibitors (e.g.,        β-aminopropionitrile and anti-LOXL2 antibodies [e.g., simtuzumab        and AB-0023])}, procollagen-proline dioxygenase (or prolyl        4-hydroxylase, which forms more stable hydroxylated collagen)        inhibitors (e.g., malotilate, HOE-077, S-0885 and S-4682), and        procollagen glucosyltransferase (or galactosylhydroxylysine        glucosyltransferase, which is important for collagen fibril        formation) inhibitors (e.g., malotilate);    -   inhibitors of pro-fibrotic growth factors (e.g., transforming        growth factor-beta [including TGF-β1], connective tissue growth        factor [CTGF] and platelet-derived growth factor [including        PDGF-B, PDGF-C and PDGF-D]) or their production, activation or        signaling, including TGF-β inhibitors {e.g., anti-TGF-β        antibodies (e.g., fresolimumab [GC1008] and CAT-192) and soluble        TGF-β receptors (e.g., sTGFβR1, sTGFβR2 and sTGFβR3)}, TGFβR        antagonists {e.g., TGFβR1 (ALK5) antagonists (e.g., galunisertib        [LY-2157299], EW-7197, GW-788388, LY-2109761, SB-431542,        SB-525334, SKI-2162, SM-16, and inhibitory Smads [e.g., Smad6        and Smad7])}, anti-CTGF antibodies (e.g., FG-3019), PDGF        inhibitors (e.g., squalamine, PP1, anti-PDGF aptamers [e.g.,        E10030], anti-PDGF antibodies [e.g., those targeting PDGF-B,        PDGF-C and PDGF-D], and soluble PDGF receptors [e.g., sPDGFRα        and sPDGFRβ]), PDGFR (e.g., PDGFRα or/and PDGFRβ) antagonists        (e.g., anti-PDGFR antibodies [e.g., REGN2176-3]), bone        morphogenic protein-7 (BMP-7) (directly antagonizes TGF-β1        signaling and Smad3 activation, and promotes        mesenchymal-to-epithelial transition), N-acetyl-L-cysteine        (inhibits TGF-β expression and activation by monomerization of        the biologically active TGF-β dimer),        S-nitroso-N-acetyl-L-cysteine (suppresses TGF-β1), L-carnitine        (reduces PDGF-B expression), epigallocatechin-3-gallate        (suppresses activation of Smad2 and Smad3 [and Akt]), galectin-7        (binds to and inhibits phosphorylated Smad2 and Smad3),        Leu-Ser-Lys-Leu (inhibits TGF-β1 activation), α-lipoic acid        (inhibits TGF-β signaling via inhibition of Smad3 and AP-1),        luteolin (inhibits TGF-β and PDGF signaling), melatonin        (inhibits TGF-β and CTGF expression and Smad3 activation),        naringenin (suppresses Smad3 expression and activation), niacin        (reduces TGF-β expression), pirfenidone (reduces TGF-β        production), quercetin (reduces expression of TGF-β1, CTGF,        PDGF-B and Smad3), resveratrol (suppresses TGF-β expression),        simvastatin (reduces TGF-β1 [and α-SMA] expression), taurine        (reduces TGF-β1 [and α-SMA] expression), tranilast (inhibits        TGF-β1 expression), vitamin E and analogs thereof (e.g.,        α-tocopherol and trolox, both of which suppress TGF-β        expression), and α_(V)β₆ integrin (which activates TGF-β1)        inhibitors (e.g., anti-α_(V)β₆ antibodies such as STX-100);    -   receptor tyrosine kinase (TK) inhibitors, including epidermal        growth factor receptor (EGFR) TK inhibitors (e.g., afatinib,        brigatinib, erlotinib, gefitinib, icotinib, lapatinib,        osimertinib and isoflavones [e.g., genistein]), PDGFR TK        inhibitors (e.g., crenolanib, imatinib and AG-1295), dual        FGFR/VEGFR TK inhibitors (e.g., brivanib and brivanib        alaninate), dual PDGFR/VEGFR TK inhibitors (e.g., axitinib,        sorafenib, sunitinib, vatalanib and X-82), and triple        FGFR/PDGFR/VEGFR TK inhibitors (e.g., nintedanib and pazopanib);    -   anti-EGFR antibodies, such as cetuximab, matuzumab, nimotuzumab,        panitumumab and zalutumumab;    -   anti-inflammatory agents, including those listed above, such as        anti-inflammatory cytokines (e.g., IL-10), inhibitors of        pro-inflammatory cytokines or their receptors or their        production (e.g., TNF-α [e.g., an anti-TNF-α antibody such as        infliximab or an immunomodulator such as pentoxifylline], IL-10,        IL-6 and MCP-1), colchicine, curcuminoids (e.g., curcumin),        malotilate, nintedanib, pirfenidone and tranilast; antioxidants,        including those listed above, such as vitamins and analogs        thereof (e.g., vitamin E and analogs thereof such as        α-tocopherol and trolox), sulfur-containing antioxidants (e.g.,        glutathione, NAC, SNAC, SAC [also suppresses α-SMA expression]        and SAM), ROS and radical scavengers (e.g., melatonin and        glutathione), Nrf2 activators {e.g., fumarates (e.g., dimethyl        and monomethyl fumarate), trichostatin A, and triterpenoids        (e.g., oleanolic acid analogs [supra, such as TP-225])}, and        omega-3 fatty acids and esters thereof (e.g., Lovaza fish oil);    -   antagonists of the renin-angiotensin-aldosterone system (RAAS),        including those listed above, such as renin inhibitors (e.g.,        aliskiren [reduces hepatic steatosis, oxidative stress,        inflammation and fibrosis]), ACE inhibitors (e.g., captopril        [inhibits fibroblast proliferation and reduces fibrotic lung        response] and perindopril [inhibits liver fibrosis]), and        angiotensin II receptor type 1 (AT₁) antagonists (e.g.,        candesartan [inhibits liver fibrosis], irbesartan and losartan)        (activation of AT₁ by angiotensin II activates PLC, leading to        increased cytosolic Ca²⁺ concentration and hence PKC        stimulation, also activates tyrosine kinases and promotes ECM        formation);    -   inhibitors of the accumulation or effects of advanced glycation        end-products (AGEs, which inter alia increase arterial stiffness        and stimulate mesangial matrix expansion), including inhibitors        of AGE formation (e.g., aminoguanidine, aspirin, benfotiamine,        carnosine, α-lipoic acid, metformin, pentoxifylline, pimagedine,        pioglitazone, pyridoxamine, taurine and vitamin C), cleavers of        AGE crosslinks (e.g., aminoguanidine, N-phenacylthiazolium        bromide, rosmarinic acid, alagebrium [ALT-711], ALT-462, ALT-486        and ALT-946), and inhibitors of AGE effects (e.g., natural        phenols such as curcumin and resveratrol);    -   other kinds of antifibrotic agents, including RGD mimetics and        analogs (inhibit adhesion of fibroblasts and immune cells to ECM        glycoproteins) (e.g., NS-11, SF-6,5 and GRGDS), galectin-3        (which is critical for liver fibrosis) inhibitors (e.g.,        GM-CT-01 and GR-MD-02), marinobufagenin inhibitors (e.g.,        resibufogenin, spironolactone and canrenone), trichostatin A        (inhibits TGFβ1-induced epithelial-to-mesenchymal transition),        and PPAR-γ agonists (e.g., thiazolidinediones [supra]); and    -   analogs, derivatives, fragments and salts thereof.

Non-alcoholic fatty liver disease (NAFLD), the most common liverdisorder in developed countries, is characterized by fatty liver thatoccurs when fat, in particular free fatty acids and triglycerides,accumulates in the liver cells (hepatic steatosis) due to causes otherthan excessive alcohol consumption, such as nutrient overload, highcaloric intake and metabolic dysfunction (e.g., hyperlipidemia andimpaired glucose control). A liver can remain fatty without disturbingliver function, but a fatty liver can progress to become non-alcoholicsteatohepatitis (NASH), a condition in which steatosis is accompanied byinflammation, hepatocyte ballooning and cell injury with or withoutfibrosis of the liver. Fibrosis is the strongest predictor of mortalityfrom NASH. NASH is the most extreme form of NAFLD. NASH is a progressivedisease, with about 20% of patients developing cirrhosis of the liverand about 10% dying from a liver disease, such as cirrhosis or a livercancer (e.g., hepatocellular carcinoma).

NAFLD, including NASH, is associated with obesity, metabolic syndromeand insulin resistance. For instance, insulin resistance contributes toprogression of fatty liver to hepatic inflammation and fibrosis and thusNASH. Furthermore, obesity drives and exacerbates NASH, and weight losscan alleviate NASH.

In some embodiments, one or more NR/NAR derivatives described herein areused in combination with one or more additional therapeutic agents totreat NAFLD, such as NASH. In some embodiments, the one or moreadditional therapeutic agents are selected from antidiabetic agents,anti-obesity agents, anti-inflammatory agents, antifibrotic agents,antioxidants, and combinations thereof.

Therapeutic agents that can be used to treat NAFLD (e.g., NASH) includewithout limitation:

-   -   PPAR agonists, including PPAR-δ agonists (e.g., MBX-8025,        elafibranor [dual PPAR-α/δ agonist], lanifibranor [triple        PPAR-α/δ/γ agonist] and GW501516 [dual PPAR-β/δ agonist]) and        PPAR-γ agonists (e.g., thiazolidinediones such as pioglitazone        and rosiglitazone, and saroglitazar [dual PPAR-α/γ        agonist])—PPAR-δ and -γ agonism increases insulin sensitivity,        PPAR-α agonism reduces liver steatosis and PPAR-δ agonism        inhibits activation of macrophages and Kupffer cells;    -   GLP-1R agonists (e.g., exenatide, liraglutide and semaglutide),        dual GLP-1R/GCGR agonists (e.g., MEDI0382 and SP-1373) and dual        GLP-1R/GIPR agonists—such agonists reduce liver steatosis,        inflammation and fibrosis;    -   farnesoid X receptor (FXR) agonists, such as obeticholic acid,        EDP-305, GS-9674, LJN452 and TERN-101—FXR agonists reduce liver        gluconeogenesis, lipogenesis, steatosis and fibrosis;    -   thyroid hormone receptor-beta agonists, such as MGL-3196 and        VK2809—THR-β agonists reduce liver steatosis;    -   fibroblast growth factor 19 (FGF19) and analogs and derivatives        thereof, such as NGM-282-FGF19 analogs reduce liver        gluconeogenesis and steatosis;    -   fibroblast growth factor 21 (FGF21) and analogs and derivatives        thereof, such as BMS-986036 and PF-05231023-FGF21 analogs reduce        liver steatosis, cell injury and fibrosis;    -   HMG-CoA reductase inhibitors, including statins (e.g.,        atorvastatin, pitavastatin and rosuvastatin)—statins reduce        steatohepatitis and fibrosis;    -   ACC inhibitors, such as NDI-010976 (liver-targeted) and        GS-0976-ACC inhibitors reduce de novo lipogenesis and liver        steatosis;    -   SCD-1 inhibitors, such as aramchol—SCD-1 inhibitors reduce liver        steatosis and increase insulin sensitivity;    -   ATP citrate lyase inhibitors, such as bempedoic acid—ACL        inhibitors reduce reduce liver steatosis;    -   ketohexokinase inhibitors, such as PF-06835919—KHK inhibitors        reduce liver lipogenesis and inflammation;    -   SGLT2 inhibitors, such as canagliflozin, dapagliflozin,        empagliflozin, ipragliflozin and luseogliflozin—SGLT2 inhibitors        reduce body weight, liver ALT level and fibrosis;    -   vascular adhesion protein-1 (VAP-1) inhibitors, such as        N-[4-(2-{4-[(2-amino-1H-imidazol-4-yl)methyl]phenyl}ethyl)thiazol-2-yl]acetamide        hydrochloride, 2-bromoethylamine, semicarbazide, ASP8232,        BI-1467335 (PXS-4728A), PXS-4681A, PRX-167700 and TERN-201—VAP-1        inhibitors increase insulin sensitivity and reduce liver        inflammation and fibrosis;    -   antagonists of CCR2 or/and CCR5, such as        cenicriviroc—antagonists of CCR2 (binds to CCL2 [MCP1]) and CCR5        (binds to CCL5 [RANTES]) inhibit activation and migration of        inflammatory cells (e.g., macrophages) to the liver and reduce        liver fibrosis;    -   apoptosis inhibitors, including apoptosis signal-regulating        kinase 1 (ASK1) inhibitors (e.g., selonsertib) and caspase        inhibitors (e.g., emricasan [pan-caspase inhibitor])—apoptosis        inhibitors reduce liver steatosis and fibrosis;    -   TGF-β inhibitors (e.g., fresolimumab) and TGF-βR antagonists        (e.g., galunisertib)—they reduce liver fibrosis;    -   lysyl oxidase-like 2 (LOXL2) inhibitors, such as        simtuzumab—LOXL2 is a key matrix enzyme in collagen formation        and is highly expressed in the liver;    -   galectin-3 inhibitors, such as GR-MD-02 and TD139—galectin-3 is        critical for development of liver fibrosis;    -   inhibitors of lysophosphatidic acid (LPA) or receptors therefor        (e.g., LPAR1) or the production thereof, such as autotaxin        inhibitors (e.g., GLPG1690, HA-130, ONO-8430506, PF-8380,        S-32826) and anti-autotaxin DNA aptamers (e.g., RB011 and        RB014)—such inhibitors inhibit myofibroblast proliferation and        hence liver fibrosis;    -   antioxidants, including vitamin E (e.g., α-tocopherol) and        scavengers of ROS and free radicals (e.g., cysteamine,        glutathione, melatonin and pentoxifylline [also        anti-inflammatory via inhibition of TNF-α and        phosphodiesterases])—vitamin E reduces liver steatosis,        hepatocyte ballooning and lobular inflammation; and    -   analogs, derivatives and salts thereof.

In some embodiments, the one or more additional therapeutic agents fortreatment of NAFLD (e.g., NASH) are or include a PPAR agonist (e.g., aPPAR-δ agonist such as elafibranor or/and a PPAR-γ agonist such aspioglitazone), a HMG-CoA reductase inhibitor (e.g., a statin such asrosuvastatin), an FXR agonist (e.g., obeticholic acid) or an antioxidant(e.g., vitamin E), or any combination thereof. In certain embodiments,the one or more additional therapeutic agents for treatment of NAFLD(e.g., NASH) are or include vitamin E or/and pioglitazone.

In other embodiments, one or more NR/NAR derivatives of the disclosureare used in combination with one or more anticancer agents to treat atumor (benign or malignant) or a cancer. For brevity, the term“anticancer agents” as used herein encompasses antitumor agents. In someembodiments, the one or more anticancer agents are or include radiationtherapy, chemotherapy or cancer immunotherapy, or any combination or allthereof.

In some embodiments, the chemotherapeutic agent is or includes a PARPinhibitor, a TGF-β inhibitor or a cytotoxic agent, or any combination orall thereof. Examples of PARP inhibitors are described above. In certainembodiments, the PARP inhibitor is olaparib.

Transforming growth factor-beta (TGF-β) is a cytokine that promotes thegrowth of pre-cancer and cancer cells, angiogenesis and invasion ofcancer cells. TGF-β also converts effector T-cells, which normallyattack cancer cells with an inflammatory (immune) reaction, intoregulatory T-cells that suppress the immune reaction. An increase inTGF-β expression often correlates with the malignancy of many cancers.Therefore, inhibitors of TGF-β or the production, activation orsignaling thereof can be used to treat tumors and cancers. Since TGF-β(including TGF-β1) is also a major driver of collagen production andfibrosis, inhibitors of TGF-β or the production, activation or signalingthereof are listed among antifibrotic agents above.

Anticancer cytotoxic agents include without limitation:

-   -   alkylating agents, including aziridines (e.g., diaziquone,        mytomycin and thiotepa), nitrogen mustards (e.g., mannomustine,        mustine [mechlorethamine or chlormethine], aniline mustard,        bendamustine, benzoic acid mustard, chlorambucil, C6-galactose        mustard, melphalan, ossichlorin [nitromin], prednimustine,        uramustine, nitrogen mustard carbamates [e.g., estramustine],        and oxazaphosphorines [e.g., cyclophosphamide, ifosfamide,        mafosfamide, and trofosfamide]), nitrosoureas (e.g., carmustine,        fotemustine, lomustine, nimustine, N-nitroso-N-methylurea,        ranimustine, semustine and streptozotocin), platinum-containing        compounds (e.g., cisplatin, carboplatin and oxaliplatin),        alkylsulfonates (e.g., busulfan, mannosulfan and treosulfan),        hydrazines (e.g., dacarbazine and procarbazine),        imidazotetrazines (e.g., mitozolomide and temozolomide), and        triazines (e.g., hexamethylmelamine [altretamine]);    -   cytotoxic antibiotics, including anthracyclines (e.g.,        aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin,        mitoxantrone, pirarubicin and valrubicin), actinomycins (e.g.,        actinomycin D), bleomycins (e.g., bleomycins A₂ and B₂),        mitomycins (e.g., mitomycin C), and plicamycins;    -   antimetabolites, including antifolates (e.g., aminopterin,        methotrexate, pemetrexed and pralatrexate), deoxynucleoside        analogs (e.g., 5-azacytidine [azacitidine],        5-aza-2′-deoxycytidine [decitabine], cladribine, clofarabine,        cytarabine, decitabine, fludarabine, gemcitabine, nelarabine and        pentostatin), fluoropyrimidines (e.g., 5-fluorouracil,        capecitabine, 5-fluoro-5′-deoxyuridine [doxifluridine] and        trifluridine), and thiopurines (e.g., thioguanine, azathioprine        and mercaptopurine);    -   antimicrotubule agents, including dolastatins (e.g., dolastatin        15), epothilones (e.g., epothilones A-F), halichondrins (e.g.,        halichondrin B) and analogs thereof (e.g., eribulin),        maytansine, maytansinoids (e.g., ansamitocin, emtansine,        mertansine, ravtansine and soravtansine), taxanes (e.g.,        paclitaxel, docetaxel and cabazitaxel), vinca alkaloids (e.g.,        vinblastine, vincristine, vindesine, vinflunine and        vinorelbine), colchicine, nocodazole, podophyllotoxin and        rhizoxin;    -   histone deacetylase inhibitors, including trichostatins (e.g.,        trichostatin A), romidepsin, panobinostat and vorinostat;    -   kinase inhibitors, including bortezomib, erlotinib, gefitinib,        imatinib, vemurafenib, vismodegib, curcumin, cyclocreatine,        deguelin, fostriecin, hispidin, staurosporine and derivatives        thereof (e.g., midostaurin), and tyrphostins (e.g., tyrphostins        AG 34 and AG 879);    -   topoisomerase I inhibitors, including camptothecin, irinotecan        and topotecan;    -   topoisomerase II-targeting agents, including topoisomerase II        poisons (e.g., etoposide, tafluposide, teniposide, doxorubicin        and mitoxantrone) and topoisomerase II inhibitors (e.g.,        novobiocin, merbarone and aclarubicin);    -   DNA or RNA synthesis inhibitors, including        3-amino-1,2,4-benzotriazine 1,4-dioxide, cytosine        β-D-arabinofuranoside, 5,6-dichlorobenzimidazole        1-β-D-ribofuranoside, ganciclovir and hydroxyurea;    -   protein synthesis inhibitors, including homoharringtonine;    -   cell growth and differentiation regulators, including retinoids        (e.g., all-trans retinol [vitamin A], 11-cis retinol, all-trans        retinal [vitamin A aldehyde], 11-cis retinal, all-trans retinoic        acid [tretinoin], 9-cis-retinoic acid [alitretinoin], 11-cis        retinoic acid, 13-cis-retinoic acid [isotretinoin], all-trans        retinyl esters, etretinate, acitretin, adapalene, bexarotene and        tazarotene);    -   cell proliferation inhibitors, including mTOR inhibitors (e.g.,        everolimus, novolimus, ridaforolimus, sirolimus [rapamycin],        temsirolimus, umirolimus [biolimus A9] and zotarolimus),        apigenin, cholecalciferol (vitamin D₃) and sex hormone-binding        globulin;    -   apoptosis inducers, including        17-allylamino-17-demethoxygeldanamycin, melatonin, mevinolin,        psoralen, thapsigargin, troglitazone, inhibitors of histone        deacetylases (e.g., romidepsin), and RXR agonists (supra, such        as retinoids [e.g., bexarotene]); and    -   analogs, derivatives and salts thereof.

Cancer immunotherapeutic agents include agents that block immunecheckpoints and agents that stimulate the immune system. In certainembodiments, the cancer immunotherapeutic agent is or includes ananti-PD-1 antibody or an anti-PD-L1 antibody, or/and an anti-CTLA-4antibody.

Anticancer agents that block immune checkpoints include withoutlimitation:

-   -   inhibitors of programmed cell death 1 (PD-1) receptor or ligands        thereof (e.g., PD-L1 and PD-L2), including anti-PD-1 antibodies        (e.g., cemiplimab, nivolumab, pembrolizumab, pidilizumab and        MEDI-0680 [AMP-514]), anti-PD-1 fusion proteins (e.g., AMP-224        [containing an F_(c) Ab domain and PD-L2]), anti-PD-L1        antibodies (e.g., avelumab, atezolizumab, durvalumab, and        BMS-936559 [MDX-1105]), and small-molecule inhibitors of PD-L1        (e.g., BMS-1001 and BMS-1166);    -   inhibitors of cytotoxic T lymphocyte-associated protein 4        (CTLA-4) receptor or ligands thereof, including anti-CTLA-4        antibodies (e.g., ipilimumab and tremelimumab);    -   inhibitors of killer cell immunoglobulin-like receptors (KIRs)        or ligands thereof, including anti-KIR antibodies (e.g.,        lirilumab);    -   inhibitors of lymphocyte activation gene 3 (LAG-3) receptor or        ligands thereof, including anti-LAG-3 antibodies (e.g.,        BMS-986016 and GSK2831781);    -   inhibitors of T-cell immunoglobulin and mucin domain-containing        3 (TIM-3, also called hepatitis A virus cellular receptor 2        [HAVCR2]), including anti-TIM3 antibodies (e.g., LY3321367,        MBG453 and TSR-022);    -   inhibitors of indoleamine 2,3-dioxygenase (IDO or IDO1),        including indoximod (1-methyl-D-tryptophan), navoximod,        α-methyl-tryptophan, β-carboline (9H-pyrido[3,4-b]indole or        norharmane), epacadostat (INCB024360), BMS-986205, NLG-919, and        COX-2 inhibitors (e.g., coxibs [supra], which down-regulate the        expression of IDO); and    -   analogs, derivatives, fragments and salts thereof.

Anticancer agents that stimulate the immune system include, but are notlimited to:

-   -   agonists of tumor necrosis factor receptor superfamily member 4        (TNFRSF4, OX40 or CD134), including OX40-targeting antibodies        (e.g., MEDI-6469 and 9B12) and ligands for OX40 (e.g., OX40L);    -   agonists of TNFRSF member 5 (TNFRSF5 or CD40), including        CD40-targeting antibodies (e.g., dacetuzumab and CP-870,893) and        ligands for CD40 (e.g., CD40L [CD154]);    -   agonists of TNFRSF member 9 (TNFRSF9, 4-1BB or CD137), including        4-1BB-targeting antibodies (e.g., urelumab and PF-05082566) and        ligands for 4-1BB (e.g., 4-1BBL);    -   agonists of TNFRSF member 18 (TNFRSF18, glucocorticoid-induced        TNFR-related protein [GITR] or CD357), including GITR-targeting        antibodies (e.g., DTA-1 and TRX518) and ligands for GITR (e.g.,        GITRL);    -   agonists of toll-like receptors (TLRs), including ligands for        TLR9 (e.g., unmethylated CpG oligodeoxynucleotides [CpG ODNs],        such as agatolimod);    -   cytokines and hormones that stimulate immune cells, including        IL-6 and epinephrine (stimulator of, e.g., natural killer        cells); and    -   analogs, derivatives, fragments and salts thereof.

Angiogenesis is important for the transition of a benign tumor to amalignant tumor (i.e., a cancer), and for metastasis of a cancer. Thus,anticancer agents include angiogenesis inhibitors. Angiogenesisinhibitors include without limitation inhibitors of vascular endothelialgrowth factors (VEGFs) {e.g., squalamine, ACU-6151, LHA-510, PAN-90806,decorin, anti-VEGF antibodies and fragments thereof (e.g., bevacizumab,ranibizumab, brolucizumab, ENV1305, ESBA903 and ESBA1008), anti-VEGFimmunoconjugates (e.g., KSI-301), anti-VEGF aptamers (e.g., pegaptanib),anti-VEGF designed ankyrin repeat proteins (DARPins) (e.g., abiciparpegol), soluble VEGFRs (e.g., sVEGFR1), and soluble fusion proteinscontaining one or more extracellular domains of one or more VEGFRs(e.g., VEGFR1, VEGFR2 and VEGFR3) (e.g., aflibercept, conbercept andOPT-302)}, inhibitors of receptors for VEGFs (e.g., VEGFR1 and VEGFR2)(e.g., axitinib, fruquintinib, pazopanib, regorafenib, sorafenib,sunitinib, tivozanib, isoxanthohumol, pristimerin, KPI-285, PF-337210,PP1, TG100572, X-82, D-(LPR), decorin, and anti-VEGFR antibodies andfragments thereof [e.g., ramucirumab]), inhibitors of platelet-derivedgrowth factors (PDGFs) {e.g., squalamine, PP1, decorin, anti-PDGFaptamers (e.g., E10030 and pegpleranib), anti-PDGF antibodies andfragments thereof (e.g., rinucumab), and soluble PDGFRs} or receptorstherefor (PDGFRs) (e.g., axitinib, imatinib, nilotinib, pazopanib,sorafenib, sunitinib, X-82, and anti-PDGFR antibodies and fragmentsthereof [e.g., REGN2176-3]), inhibitors of fibroblast growth factors(FGFs) (e.g., squalamine, decorin, anti-FGF antibodies and fragmentsthereof, anti-FGF aptamers and soluble FGFRs) or receptors therefor(FGFRs) (e.g., erdafitinib, pazopanib and anti-FGFR antibodies andfragments thereof), inhibitors of angiopoietins (e.g., decorin,anti-angiopoietin antibodies and fragments thereof such as nesvacumaband REGN910-3, and soluble angiopoietin receptors) or receptors therefor(e.g, antibodies and fragments thereof against angiopoietin receptors),bispecific anti-VEGF/anti-angiopoietin antibodies and fragments thereof(e.g., anti-VEGF/anti-angiopoietin-2 antibodies such as ABP-201 andRG7716), inhibitors of integrins (e.g., ALG-1001, JSM-6427, SF0166, andanti-integrin antibodies and fragments thereof), tissue factor (TF)inhibitors (e.g., anti-TF antibodies and fragments thereof and fusionproteins thereof [e.g., ICON-1]), kallikrein inhibitors (e.g.,avoralstat, ecallantide, BCX7353, KVD001, and anti-kallikrein antibodiesand fragments thereof [e.g., DX-2930]), serine/arginine-protein kinase 1(SRPK1) inhibitors (e.g., SPHINX31), Src kinase inhibitors (e.g.,SKI-606 and TG100572), anecortave (anecortave acetate), angiostatin(e.g., angiostatin K1-3), α_(V)β₃ inhibitors (e.g., etaracizumab),apoA-I mimetics (e.g., L-4F and L-5F), apoE mimetics (e.g., apoEdp),azurin(50-77) (p28), berberine, bleomycins, borrelidin,carboxyamidotriazole, cartilage-derived angiogenesis inhibitors (e.g.,chondromodulin I and troponin I), castanospermine, CM101,corticosteroids (including glucocorticoids), cyclopropene fatty acids(e.g., sterculic acid), α-difluoromethylornithine, endostatin,everolimus, fumagillin, genistein, heparin, interferon-α,interleukin-12, interleukin-18, itraconazole, KV11, linomide,2-methoxyestradiol, pigment epithelium-derived factor (PEDF), plateletfactor-4, PPAR-α agonists (e.g., fibrates), PPAR-γ agonists (e.g.,thiazolidinediones), prolactin, rapamycin (sirolimus),sphingosine-1-phosphate inhibitors (e.g., sonepcizumab), squalene,staurosporine, angiostatic steroids (e.g., tetrahydrocortisol) plusheparin, stilbenoids, suramin, SU5416, tasquinimod, tecogalan,tetrathiomolybdate, thalidomide and derivatives thereof (e.g.,lenalidomide and pomalidomide), thiabendazole, thrombospondins (e.g.,thrombospondin 1), TNP-470, tranilast, triterpenoids (e.g., oleanolicacid analogs [supra] such as TP-225), (+)-TBE-B, tumstatin and fusionproteins thereof (e.g., OCU200), vasostatin, vasostatin 48, WithaferinA, and analogs, derivatives, fragments and salts thereof.

Other kinds of anticancer agents include, but are not limited to:

-   -   drug-efflux pump inhibitors, including β-glycoprotein inhibitors        (e.g., mifepristone and verapamil);    -   cell adhesion inhibitors, such as cimetidine;    -   Golgi apparatus disruptors, such as brefeldins (e.g., brefeldin        A);    -   ionizing radiation, such as X-ray;    -   radiopharmaceuticals, such as ¹³¹I-iodide, ¹³¹I-MIBG        (m-iodobenzylguanidine), ²²³Ra-dichloride, ¹⁵³Sm-EDTMP        (ethylenediaminotetramethylenephosphoric acid), and        ⁸⁹Sr-chloride;    -   sensitizers of cancer cells to radiation, including PARP        inhibitors (infra), berberine and indomethacin;    -   enhancers of cell survival after treatment with cytotoxic drugs        or radiation, such as pifithrin-α;    -   vaccines, including those that stimulate the immune system to        recognize proteins produced by tumor/cancer cells and thereby to        attack tumor/cancer cells; and    -   analogs, derivatives and salts thereof.

An NR or NAR derivative can enhance the immune response to an acute orchronic viral, bacterial or fungal infection when used in conjunctionwith an antiviral, antibacterial or antifungal agent. In certainembodiments, the antibiotic is ethionamide and optionally SMARt-420 fortreatment of, e.g., tuberculosis. Ethionamide has antibiotic propertiesagainst mycobacteria such as M. tuberculosis. SMARt-420 reversesresistance of, e.g., M. tuberculosis to ethionamide and increases thebacteria's sensitivity to ethionamide.

An NR or NAR derivative can also enhance and direct the adaptive immuneresponse to a vaccine antigen, thereby improving the effectiveness ofthe vaccine. An NR or NAR derivative can be utilized as a component of avaccine adjuvant. In certain embodiments, an NR or NAR derivative isadministered in combination with a vaccine to a subject in order toenhance the effectiveness of the vaccine.

The optional additional therapeutic agent(s) independently can beadministered in any suitable mode, including without limitation oral,parenteral (including intramuscular, intradermal, subcutaneous,intravascular, intravenous, intra-arterial, intraperitoneal,intracavitary, intramedullary, intrathecal and topical), and topical(including dermal/epicutaneous, transdermal, mucosal, transmucosal,intranasal [e.g., by nasal spray or drop], pulmonary [e.g., by oral ornasal inhalation], ocular [e.g., by eye drop], buccal, sublingual,rectal [e.g., by suppository] and vaginal [e.g., by suppository]). Incertain embodiments, an additional therapeutic agent is administeredorally. In other embodiments, an additional therapeutic agent isadministered parenterally (e.g., intravenously, subcutaneously orintramuscularly).

The optional additional therapeutic agent(s) independently can beadministered in any suitable frequency, including without limitationdaily (one, two or more times per day), once every two or three days,twice weekly or once weekly, or on a pro re nata (as-needed) basis,which can be determined by the treating physician. The dosing frequencycan depend on, e.g., the mode of administration chosen. The length oftreatment with the optional additional therapeutic agent(s) can bedetermined by the treating physician and can independently be, e.g., atleast about 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks (1month), 6 weeks, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years,4 years, 5 years or longer.

The therapeutically effective amount of, the frequency and route ofadministration of, and the length of treatment with, an optionaladditional therapeutic agent can be based in part on recommendations forthat therapeutic agent and can be determined by the treating physician.

In some embodiments, an NR or NAR derivative and an additionaltherapeutic agent are administered in separate pharmaceuticalcompositions. In other embodiments, an NR or NAR derivative and anadditional therapeutic agent are administered in the same pharmaceuticalcomposition, such as in a fixed-dose combination dosage form. In someembodiments, the fixed-dose combination dosage form is formulated forcontrolled-release, slow-release or sustained-release of the NR or NARderivative or/and the additional therapeutic agent. In certainembodiments, the fixed-dose combination dosage form is formulated fororal administration, such as once or twice daily and such as in the formof a tablet, capsule or pill. In other embodiments, the fixed-dosecombination dosage form is formulated for parenteral administration,such as intravenously, subcutaneously or intramuscularly.

Combination Therapies with PARP Inhibitors

When activated by DNA damage, poly(ADP-ribose) polymerase (PARP)recruits other proteins that repair single-stranded DNA breaks(“nicks”). PARP activity is necessary for repair of DNA nicks. PARPexpression and activity are upregulated under diverse conditions thatlead to DNA damage and ultimately cell injury or cell death, includinghypoxia. However, PARP is a major consumer of NAD⁺ in the cell, andmarkedly increased PARP activity can deplete NAD and cause profoundmitochondrial and cellular dysfunction. Therefore, PARP inhibition canincrease NAD⁺ level (e.g., in mitochondria, the cytosol or/and thenucleus, such as total cellular NAD⁺ level) and thereby can enhancemitochondrial function (e.g., oxidative metabolism), mitochondrialbiogenesis and cellular function (e.g., increase the activity ofsirtuins such as SIRT1 and SIRT3).

PARP inhibitors are currently approved as antitumor/anticancer agents.DNA damage occurs countless times during each cell cycle, and failure torepair damaged DNA leads to the death of tumor/cancer cells. Some PARPinhibitors mainly block PARP enzyme activity and do not trap PARP onDNA, while other PARP inhibitors both block PARP enzyme activity and actas PARP poison. In the latter case, PARP bound to a PARP inhibitorbecomes trapped at the site of a DNA nick, and such a trapped PARP-DNAcomplex (PARP poison) is more toxic to cells than the unrepairedsingle-strand DNA breaks that accumulate in the absence of PARP activitybecause it blocks DNA replication. PARP inhibitors include withoutlimitation niraparib, olaparib, pamiparib (BGB290), rucaparib,talazoparib, veliparib, 4-amino-1,8-naphthalimide, CEP9722, E7016, PJ34,and analogs, derivatives and salts thereof.

The inventors have surprisingly discovered that the combination ofnicotinamide riboside plus olaparib at a dose much lower than itschemotherapeutic dose synergistically increases NAD⁺ level (e.g., inmitochondria, the cytosol or/and the nucleus, such as total cellularNAD⁺ level) and provides cytoprotection (reduces cytotoxicity) under DNAdamage-inducing conditions (see Example 6 below). Without intending tobe bound by theory, low-level PARP inhibition by a PARP inhibitor (e.g.,olaparib) at a low dose can reduce the rate of NAD⁺ consumption by PARP,increase NAD⁺ level and hence enhance mitochondrial and cellularfunction and provide cytoprotection. Moreover, low-level PARP inhibitioncan avoid the trapping of PARP at the site of a DNA nick, therebyallowing the cellular DNA-repair machinery to repair damaged DNA.

In some embodiments, one or more nicotinyl riboside compounds incombination with a PARP inhibitor increase NAD⁺ level (e.g., totalcellular NAD⁺ level, such as that in target cells) by at least about20%, 30%, 50%, 100% (2-fold), 150%, 200% (3-fold), 4-fold, 5-fold,6-fold, 7-fold, 8-fold, 9-fold or 10-fold in vitro, ex vivo or in vivo.In certain embodiments, one or more nicotinyl riboside compounds incombination with a PARP inhibitor increase NAD⁺ level (e.g., totalcellular NAD⁺ level, such as that in target cells) by at least about50%, 100% (2-fold), 3-fold or 5-fold in vitro, ex vivo or in vivo.

In further embodiments, one or more nicotinyl riboside compounds incombination with a PARP inhibitor increase the number of viable cells(e.g., target cells) by at least about 10%, 20%, 30%, 50%, 100%(2-fold), 150%, 200% (3-fold), 4-fold or 5-fold in vitro, ex vivo or invivo. In certain embodiments, one or more nicotinyl riboside compoundsin combination with a PARP inhibitor increase the number of viable cells(e.g., target cells) by at least about 20%, 50%, 100% or 200% in vitro,ex vivo or in vivo.

In some embodiments, one or more nicotinyl riboside compounds are usedin combination with a PARP inhibitor at a dose significantly lower thanits recommended dose as an antitumor/anticancer agent to treat anon-tumor/non-cancer disease/disorder or condition disclosed herein, orto bring about a biological effect disclosed herein (e.g., increase NAD⁺level or/and provide cytoprotection). The PARP inhibitor can inhibit oneor more members of the PARP family, such as PARP-1 or/and PARP-2. Incertain embodiments, the PARP inhibitor is a selective or non-selectiveinhibitor of PARP-1. The non-tumor/non-cancer disease or condition canbe, e.g., any mitochondrial disease, mitochondria-related disease orcondition, or disease or condition characterized by acute NAD⁺ depletiondue to DNA damage described herein. In certain embodiments, the diseaseor condition is a metabolic disorder (e.g., obesity or type 2 diabetes).One or more other therapeutic agents described herein can optionally beused in combination with one or more nicotinyl riboside compounds and aPARP inhibitor. In some embodiments, the one or more nicotinyl ribosidecompounds are or comprise one or more of NR, NRH, NAR and NARH, or/andone or more NR/NAR derivatives (such as one or more NR/NAR derivativesdisclosed herein). In certain embodiments, the one or more nicotinylriboside compounds are or comprise NR or/and NRH. In other embodiments,the one or more nicotinyl riboside compounds are or comprisenicotinamide riboside triacetate (NRTA, i.e., NR having an acetate groupat each of the C-2, C-3 and C-5 positions of riboside), the reduced formof NRTA (NRHTA), nicotinic acid riboside triacetate (NARTA), or thereduced form of NARTA (NARHTA), or any combination thereof. The use ofone or more nicotinyl riboside compounds in combination with a PARPinhibitor (e.g., olaparib) at a significantly sub-chemotherapeutic dosecan synergistically increase NAD⁺ level (e.g., in mitochondria, thecytosol or/and the nucleus, such as total cellular NAD⁺ level) or/andprovide cytoprotection (e.g., reduce cell injury, damage or death), orcan have a synergistic therapeutic effect.

A PARP inhibitor at a significantly sub-chemotherapeutic dose can beused in combination with one or more nicotinyl riboside compounds totreat any non-tumor/non-cancer disease/disorder or condition associatedwith DNA damage. The DNA damage can be due to any cause, such asradiation (e.g., UV or an ionizing radiation such as X-ray), a chemical,a chemotherapeutic agent, oxidative stress or hypoxia. Thedisease/disorder or condition can be acute or chronic, and can beassociated with NAD⁺ depletion or/and cell injury, damage, degenerationor death. Such diseases/disorders and conditions include withoutlimitation diseases and conditions characterized by acute NAD⁺ depletiondue to DNA damage and described above. In certain embodiments, thedisease/disorder or condition is an acute life-threateningcardiovascular (e.g., myocardial ischemia/infarction/IRI) orcerebrovascular (e.g., cerebral ischemia/infarction/IRI) disorder, or aneurodegenerative disorder.

In some embodiments, the dose of a PARP inhibitor to treat anon-tumor/non-cancer disease/disorder or condition disclosed herein, orto bring about a biological effect disclosed herein, in combination withone or more nicotinyl riboside compounds is no more than about 10%, 5%,1%, 0.5% or 0.1% of the recommended dose of the PARP inhibitor as anantitumor/anticancer agent. In certain embodiments, the dose of a PARPinhibitor for such a use is no more than about 1% of the recommendeddose of the PARP inhibitor as an antitumor/anticancer agent. In someembodiments, the PARP inhibitor is olaparib, and the dose (e.g., per dayor per dose) of olaparib to treat a non-tumor/non-cancerdisease/disorder or condition disclosed herein, or to bring about abiological effect disclosed herein, in combination with one or morenicotinyl riboside compounds is no more than about 10 mg, 5 mg, 1 mg,0.5 mg or 0.1 mg; or is from about 0.01 or 0.1 mg to about 10 mg, fromabout 0.01 or 0.1 mg to about 1 mg, or from about 1 mg to about 10 mg;or is about 0.01-0.1 mg, 0.1-0.5 mg, 0.5-1 mg, 1-5 mg or 5-10 mg; or isabout 10 μg, 50 μg, 0.1 mg, 0.5 mg, 1 mg, 5 mg or 10 mg. In certainembodiments, the dose (e.g., per day or per dose) of olaparib for such ause is no more than about 1 mg.

A PARP inhibitor can be administered in any suitable frequency. Incertain embodiments, the PARP inhibitor is administered once or twicedaily.

The dose or therapeutically effective amount, the frequency ofadministration and the route of administration of a nicotinyl ribosidecompound used in conjunction with a low dose of a PARP inhibitor can be,e.g., any dose or therapeutically effective amount, any frequency ofadministration and any route of administration of the NR/NAR derivativesof the disclosure described herein. In some embodiments, the dose of anicotinyl riboside compound (e.g., NR, NRH, NRTA, NRHTA or an NR/NARderivative disclosed herein) is from about 1, 50 or 100 mg to about 500or 1000 mg per day, which can be administered (e.g., orally) in a singledose (e.g., N mg once daily) or in divided doses (e.g., N/2 mg twicedaily). In certain embodiments, the dose of a nicotinyl ribosidecompound is about 1-100 mg, 100-500 mg or 500-1000 mg per day, or about50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg,700 mg, 800 mg, 900 mg or 1000 mg per day. In further embodiments, thedose of a nicotinyl riboside compound is about 1-50 mg, 50-100 mg,100-200 mg, 200-300 mg, 300-400 mg or 400-500 mg per day. In certainembodiments, the dose of a nicotinyl riboside compound is from about 10,50 or 100 mg to about 200 or 300 mg per day. In some embodiments, alower dose of a nicotinyl riboside compound is used to treat a lesssevere non-tumor/non-cancer disease/disorder or condition, while ahigher dose of a nicotinyl riboside compound is used to treat a moresevere non-tumor/non-cancer disease/disorder or condition.

A nicotinyl riboside compound can be administered in any suitablefrequency. In certain embodiments, a nicotinyl riboside compound isadministered once or twice daily.

The length of treatment with a PARP inhibitor and one or more nicotinylriboside compounds to treat a non-tumor/non-cancer disease/disorder orcondition disclosed herein, or to bring about a biological effectdisclosed herein, can be determined by the treating physician. Forexample, the length of treatment with the PARP inhibitor and the one ormore nicotinyl riboside compounds can independently be at least about 1day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks (1 month), 6weeks, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years,5 years or longer. The PARP inhibitor and the one or more nicotinylriboside compounds can also be taken pro re nata (as needed).

The synergistic effects of a combination of one or more nicotinylriboside compounds and a low dose of a PARP inhibitor, such as inelevating NAD⁺ level and enhancing cytoprotection, can be exploitedprophylactically to prevent a non-tumor/non-cancer disease/disorder orcondition, or potentially to prevent a tumor or cancer. As an example,one or more nicotinyl riboside compounds and a low dose of a PARPinhibitor can be given prior to a surgery to reduce morbidity caused bygeneral anesthesia or hypoxia- or hypotension-induced cytotoxicity. Forinstance, one or more nicotinyl riboside compounds and a low dose of aPARP inhibitor can be given prior to a cardiac procedure (e.g.,angioplasty or valvular surgery) to reduce morbidity and mortality dueto hypotensive or bleeding episodes. As another example, one or morenicotinyl riboside compounds and a low dose of a PARP inhibitor can beapplied to the skin to prevent sunlight-induced skin injury.

One or more nicotinyl riboside compounds and a PARP inhibitor can beadministered to a subject via any suitable route. In certainembodiments, the one or more nicotinyl riboside compounds or/and thePARP inhibitor are administered orally. In other embodiments, the one ormore nicotinyl riboside compounds or/and the PARP inhibitor areadministered parenterally (e.g., intravenously, subcutaneously orintramuscularly). The route of administration of the one or morenicotinyl riboside compounds and the PARP inhibitor can depend in parton the disorder or condition being treated. For example, the one or morenicotinyl riboside compounds or/and the PARP inhibitor can beadministered dermally or transdermally to treat a skin disorder orcondition.

One or more nicotinyl riboside compounds and a PARP inhibitor can beadministered in the same pharmaceutical composition or in separatecompositions. In some embodiments, the one or more nicotinyl ribosidecompounds (e.g., NR or/and NRH, NRTA or/and NRHTA, or one or more NR/NARderivatives disclosed herein) and the PARP inhibitor (e.g., olaparib)are administered in a fixed-dose combination dosage form, where the doseof the PARP inhibitor is significantly lower than its recommended doseas an antitumor/anticancer agent. In some embodiments, the fixed-dosecombination dosage form is a controlled-release, slow-release orsustained-release form. In certain embodiments, the fixed-dosecombination dosage form is formulated for oral administration, such asonce or twice daily and such as in the form of a tablet, capsule orpill. In other embodiments, the fixed-dose combination dosage form isformulated for parenteral administration, such as intravenously,subcutaneously or intramuscularly. In further embodiments, the one ormore nicotinyl riboside compounds or/and the PARP inhibitor areadministered as a complex with a dendrimer (e.g., PAMAM) or via adendrimer-containing composition. The dendrimer can optionally have oneor more moieties for targeting to specific organ(s), tissue(s), celltype(s) or organelle(s), such as one or more N-acetylgalactosaminemoieties for targeting to the liver for treatment of, e.g., a liver ormetabolic disorder.

In other embodiments, one or more nicotinyl riboside compounds or/and aPARP inhibitor are utilized in ex vivo therapy, including in any ex vivotherapy described herein. In yet other embodiments, one or morenicotinyl riboside compounds and a PARP inhibitor are employed toenhance DNA editing, such as in the use of a CRISPR, transcriptionactivator-like effector nuclease (TALEN) or Arcus nuclease to promotenon-homologous end joining (NHEJ) or homology-directed repair (HDR).Low-level PARP inhibition by a low dose of a PARP inhibitor permitsrepair of single-stranded DNA breaks.

REPRESENTATIVE EMBODIMENTS

The following embodiments of the disclosure are provided to illustratethe disclosure:

1. A compound of Formula I or II:

-   wherein:    -   R¹ is hydrogen,

-   -    wherein:        -   R^(a) is hydrogen, a counterion, linear or branched C₁-C₆            alkyl, C₃-C₆ cycloalkyl, phenyl, 1-naphthyl or 2-naphthyl,            wherein the phenyl is optionally substituted with F, Cl,            —NO₂, linear or branched C₁-C₄ alkyl, —CF₃ or —O-(linear or            branched C₁-C₄ alkyl);        -   R^(b) and R^(c) at each occurrence independently are            hydrogen, linear or branched C₁-C₅ alkyl, —CH₂-phenyl,            —CH₂-3-indole or —CH₂-5-imidazole, wherein the alkyl is            optionally substituted with —OH, —OR^(j), —SH, —SR^(j),            —NH₂, —NHR^(j), —N(R^(j))₂, —NHC(═O)R^(j), —NHC(═NH)NH₂,            —C(═O)NH₂, —CO₂H or —C(═O)OR^(j), and the phenyl is            optionally substituted with —OH or —OR^(j), wherein R^(j) at            each occurrence independently is linear or branched C₁-C₄            alkyl;        -   R^(d) at each occurrence independently is hydrogen, methyl            or linear or branched C₂-C₄ alkyl;        -   R^(e) and R^(f) at each occurrence independently are            hydrogen, a counterion, linear or branched C₁-C₈ alkyl,            C₃-C₆ cycloalkyl, —CH₂—(C₃-C₆ cycloalkyl), phenyl or            —CH₂-phenyl, wherein the phenyl is optionally substituted            with F, Cl, —NO₂, linear or branched C₁-C₄ alkyl, —CF₃ or            —O-(linear or branched C₁-C₄ alkyl);        -   R^(k) is hydrogen, linear or branched C₁-C₆ alkyl,            —CH₂-phenyl, —CH₂-3-indole or —CH₂-5-imidazole, wherein the            alkyl is optionally substituted with —OH, —OR^(j), —SH,            —SR^(j), —NH₂, —NHR^(j), —N(R^(j))₂, —NHC(═O)R^(j),            —NHC(═NH)NH₂, —C(═O)NH₂, —CO₂H or —C(═O)OR^(j), and the            phenyl is optionally substituted with —OH or —OR^(j),            wherein R^(j) at each occurrence independently is linear or            branched C₁-C₄ alkyl;        -   R^(m) is hydrogen, a counterion, linear or branched C₁-C₆            alkyl, C₃-C₆ cycloalkyl, phenyl, —CH₂-phenyl or

-   -   -    wherein the phenyl is optionally substituted with F, Cl,            —NO₂, linear or branched C₁-C₄ alkyl, —CF₃ or —O-(linear or            branched C₁-C₄ alkyl); and        -   X is cis or trans —HC═CH— or —(CH₂)_(n)— optionally            substituted with —OH, —OR^(j) or —OC(═O)R^(j), wherein R^(j)            is linear or branched C₁-C₄ alkyl and n is 1, 2, 3, 4, 5 or            6;

    -   R² at each occurrence independently is hydrogen,

-   -    wherein:        -   R^(g) is hydrogen, linear or branched C₁-C₅ alkyl,            —CH₂-phenyl, —CH₂-3-indole or —CH₂-5-imidazole, wherein the            alkyl is optionally substituted with —OH, —OR^(j), —SH,            —SR^(j), —NH₂, —NHR^(j), —N(R^(j))₂, —NHC(═O)R^(j),            —NHC(═NH)NH₂, —C(═O)NH₂, —CO₂H or —C(═O)OR^(j), and the            phenyl is optionally substituted with —OH or —OR^(j),            wherein R^(j) at each occurrence independently is linear or            branched C₁-C₄ alkyl;        -   R^(h) is hydrogen, methyl or —NH₂;        -   or R^(g) and R^(h) together with the carbon atom to which            they are connected form a C₃-C₆ cycloalkyl or phenyl ring,            wherein the phenyl ring is optionally substituted with F,            Cl, —NO₂, linear or branched C₁-C₄ alkyl, —CF₃ or —O-(linear            or branched C₁-C₄ alkyl); and        -   R^(m) and X are as defined above; and    -   R³ is —NH₂, —NHR^(n), —N(R^(n))₂, —OH, —OR^(o) or

-   -    wherein:        -   R^(n) at each occurrence independently is linear or branched            C₁-C₆ alkyl or allyl, wherein the alkyl is optionally            substituted with —OH or —O-(linear or branched C₁-C₃ alkyl),            or both occurrences of R^(n) and the nitrogen atom to which            they are connected form a 3- to 6-membered heterocyclic            ring; and        -   R^(o) is a counterion, linear or branched C₁-C₆ alkyl, C₃-C₆            cycloalkyl, phenyl or —CH₂-phenyl, wherein the phenyl is            optionally substituted with F, Cl, —NO₂, linear or branched            C₁-C₄ alkyl, —CF₃ or —O-(linear or branched C₁-C₄ alkyl);

-   or a pharmaceutically acceptable salt, solvate, hydrate, clathrate,    polymorph or stereoisomer thereof,

-   with the proviso that:    -   1) R¹ and both occurrences of R² all are not hydrogen except        when R³ is

and

-   -   2) the compound of Formula I or II is not:

or a salt or stereoisomer thereof.2. The compound of Formula I or II of embodiment 1, wherein when bothoccurrences of R² are acetyl:

-   -   1) R¹ is not hydrogen; or    -   2) R³ is not —NH₂ or —OH or a salt thereof; or    -   3) R¹ is not hydrogen and R³ is not —NH₂ or —OH or a salt        thereof.        3. The compound of Formula I or II of embodiment 1, wherein when        R¹ is

-   -   1) both occurrences of R² are not hydrogen; or    -   2) R³ is not —NH₂ or —OH or a salt thereof; or    -   3) both occurrences of R² are not hydrogen and R³ is not —NH₂ or        —OH or a salt thereof.        4. The compound of Formula I or II of embodiment 1, wherein when        R¹ is

-   -   1) both occurrences of R² are not hydrogen; or    -   2) R³ is not —NH₂ or —OH or a salt thereof; or    -   3) both occurrences of R² are not hydrogen and R³ is not —NH₂ or        —OH or a salt thereof.        5. The compound of Formula I or II of embodiment 1, wherein when        R¹ is

-   -   1) both occurrences of R² are not hydrogen; or    -   2) R³ is not —NH₂ or —OH or a salt thereof; or    -   3) both occurrences of R² are not hydrogen and R³ is not —NH₂ or        —OH or a salt thereof.        6. The compound of Formula I or II of embodiment 1, wherein R¹        is hydrogen.        7. The compound of Formula I or II of embodiment 1 or 3, wherein        R¹ is

8. The compound of Formula I or II of embodiment 7, wherein R¹ is

and R^(e) is linear or branched C₁-C₆ alkyl, such as methyl, ethyl orisopropyl.9. The compound of Formula I or II of embodiment 1 or 4, wherein R¹ is

10. The compound of Formula I or II of embodiment 9, wherein R¹ is

and both occurrences of R^(f) are linear or branched C₁-C₆ alkyl, suchas methyl, ethyl or isopropyl.11. The compound of Formula I or II of embodiment 1, wherein R¹ is

12. The compound of Formula I or II of embodiment 11, wherein R¹ is

and R^(k) is linear or branched C₁-C₆ alkyl, such as methyl, ethyl orisopropyl.13. The compound of Formula I or II of embodiment 1, wherein R¹, or/andR² at either occurrence or at both occurrences, is/are

14. The compound of Formula I or II of embodiment 13, wherein:

-   -   X is trans —HC═CH—, —CH₂CH₂— or —CH(OH)CH₂—; and    -   R^(m) is hydrogen, a counterion, linear or branched C₁-C₆ alkyl        (e.g., methyl, ethyl or isopropyl) or

15. The compound of Formula I or II of embodiment 14, wherein R¹, or/andR² at either occurrence or at both occurrences, is/are selected from:

and salts thereof.16. The compound of Formula I or II of any one of the precedingembodiments, wherein R² at each occurrence independently, or at bothoccurrences, is hydrogen, —C(═O)-(linear or branched C₁-C₆ alkyl),

17. The compound of Formula I or II of embodiment 16, wherein R² at eachoccurrence independently, or at both occurrences, is hydrogen, acetyl orpropanoyl.18. The compound of Formula I or II of any one of the precedingembodiments, wherein R³ is —NH₂, —OH or a salt thereof, or

19. The compound of Formula I or II of embodiment 18, wherein R³ is

20. The compound of Formula I or II of embodiment 1 or 3, wherein:

-   -   1) R¹ is

and both occurrences of R² are acetyl or propanoyl; or

-   -   2) R¹ is

and R³ is —OH or a salt thereof; or

-   -   3) R¹ is

both occurrences of R² are acetyl or propanoyl, and R³ is —OH or a saltthereof.21. The compound of Formula I or II of embodiment 20, wherein R¹ is

and R^(e) is linear or branched C₁-C₆ alkyl, such as methyl, ethyl orisopropyl.22. The compound of Formula I or II of embodiment 1 or 3, wherein:

-   -   R¹ is

wherein R^(e) is linear or branched C₁-C₆ alkyl;

-   -   R² at both occurrences is —C(═O)-(linear or branched C₁-C₆        alkyl); and    -   R³ is —NH₂ or —OH or a salt thereof.        23. The compound of Formula I or II of embodiment 22, wherein:    -   R^(e) of the R¹ moiety is methyl, ethyl or isopropyl; and    -   R² at both occurrences is acetyl or propanoyl.        24. The compound of Formula I or II of embodiment 1 or 4,        wherein:    -   R¹ is

-   -   R² at each occurrence independently, or at both occurrences, is        hydrogen, acetyl or propanoyl; and    -   R³ is —NH₂ or —OH or a salt thereof.        25. The compound of Formula I or II of embodiment 24, wherein        for the R¹ moiety:    -   R^(b) and R^(c) at each occurrence independently are hydrogen or        linear or branched C₁-C₅ alkyl, or each pair of R^(b) and R^(o)        is hydrogen and linear or branched C₁-C₅ alkyl;    -   R^(d) at both occurrences is hydrogen; and    -   R^(f) at both occurrences is linear or branched C₁-C₆ alkyl.        26. The compound of Formula I or II of embodiment 25, wherein R¹        is

27. The compound of Formula I or II of embodiment 1 or 4, wherein:

-   -   R¹ is

wherein R^(f) at both occurrences is linear or branched C₁-C₆ alkyl;

-   -   R² at each occurrence independently, or at both occurrences, is        hydrogen or —C(═O)-(linear or branched C₁-C₆ alkyl); and    -   R³ is —NH₂ or —OH or a salt thereof.        28. The compound of Formula I or II of embodiment 27, wherein:    -   R^(f) of the R¹ moiety at both occurrences is methyl, ethyl or        isopropyl; and    -   R² at each occurrence independently, or at both occurrences, is        hydrogen, acetyl or propanoyl.        29. The compound of Formula I or II of embodiment 1, wherein:    -   R¹ is

wherein R^(k) is linear or branched C₁-C₆ alkyl;

-   -   R² at each occurrence independently, or at both occurrences, is        hydrogen or —C(═O)-(linear or branched C₁-C₆ alkyl); and    -   R³ is —NH₂ or —OH or a salt thereof.        30. The compound of Formula I or II of embodiment 29, wherein:    -   R^(k) of the R¹ moiety is methyl, ethyl or isopropyl; and    -   R² at each occurrence independently, or at both occurrences, is        hydrogen, acetyl or propanoyl.        31. The compound of Formula I or II of embodiment 1, wherein:    -   R¹ is

-   -    wherein:        -   X is cis or trans —HC═CH— or —(CH₂)_(n)— optionally            substituted with —OH, —OR^(j) or —OC(═O)R^(j), wherein R^(j)            is linear or branched C₁-C₄ alkyl and n is 1, 2, 3, 4, 5 or            6; and        -   R^(m) is hydrogen, a counterion, linear or branched C₁-C₆            alkyl or

-   -   R² at each occurrence independently, or at both occurrences, is        hydrogen or —C(═O)-(linear or branched C₁-C₆ alkyl); and    -   R³ is —NH₂ or —OH or a salt thereof.        32. The compound of Formula I or II of embodiment 31, wherein:    -   for the R¹ moiety, X is trans —HC═CH—, —CH₂CH₂— or —CH(OH)CH₂—,        and R^(m) is hydrogen, a counterion, methyl, ethyl, isopropyl or

-   -   R² at each occurrence independently, or at both occurrences, is        hydrogen, acetyl or propanoyl; and    -   R³ is —NH₂.        33. The compound of Formula I or II of embodiment 1, which is        selected from:

and pharmaceutically acceptable salts, solvates, hydrates, clathrates,polymorphs and stereoisomers thereof.34. The compound of Formula I or II of any one of the precedingembodiments, which is a compound of Formula II.35. A compound of Formula III or IV:

wherein:

-   -   R⁴ is hydrogen or —C(═O)R⁷, wherein R⁷ is linear or branched        C₁-C₆ alkyl, C₃-C₆ cycloalkyl, or phenyl optionally substituted        with F, Cl, —NO₂, linear or branched C₁-C₄ alkyl, —CF₃ or        —O-(linear or branched C₁-C₄ alkyl);    -   R⁵ at each occurrence independently is hydrogen or —C(═O)R⁸,        wherein R⁸ has the same definition as R⁷; and    -   R6 is

or a pharmaceutically acceptable salt, solvate, hydrate, clathrate,polymorph or stereoisomer thereof.36. The compound of Formula III or IV of embodiment 35, wherein:

-   -   R⁴ is hydrogen or —C(═O)R⁷, wherein R⁷ is linear or branched        C₁-C₆ alkyl; and    -   R⁵ at each occurrence independently, or at both occurrences, is        hydrogen or —C(═O)R⁸, wherein R⁸ is linear or branched C₁-C₆        alkyl.        37. The compound of Formula III or IV of embodiment 36, wherein:    -   R⁴ is hydrogen, acetyl or propanoyl; and    -   R⁵ at each occurrence independently, or at both occurrences, is        hydrogen, acetyl or propanoyl.        38. The compound of Formula III or IV of any one of embodiments        35 to 37, wherein R⁶ is

39. The compound of Formula III or IV of any one of embodiments 35 to38, which is selected from:

and pharmaceutically acceptable salts, solvates, hydrates, clathrates,polymorphs and stereoisomers thereof.40. The compound of Formula III or IV of any one of embodiments 35 to39, which is a compound of Formula IV.41. The compound of Formula I, II, III or IV of any one of the precedingembodiments, which is a trifluoromethanesulfonate (triflate or ⁻OTf)salt, an acetate (⁻OAc) salt, a trifluoroacetate (⁻OTFA) salt, a formatesalt or a chloride (Cl⁻) salt.42. The compound of Formula I, II, III or IV of any one of the precedingembodiments, which has the beta-D-riboside configuration.43. The compound of Formula I, II, III or IV of any one of the precedingembodiments, which is stereoisomerically pure (e.g., at least about 90%,95%, 98% or 99% of the compound is the indicated stereoisomer).44. The compound of Formula I, II, III or IV of any one of embodiments 1to 41, which is a racemic mixture.45. The compound of Formula I, II, III or IV of any one of embodiments 1to 41, which has the D-riboside configuration and an approximately 1:1ratio of beta-/alpha-anomers.46. A pharmaceutical or cosmetic composition comprising one or morecompounds of any one of the preceding embodiments or a pharmaceuticallyacceptable salt, solvate, hydrate, clathrate, polymorph or stereoisomerthereof, and one or more pharmaceutically acceptable carriers orexcipients.47. The pharmaceutical or cosmetic composition of embodiment 46, whichcomprises a compound of Formula II or IV.48. The pharmaceutical or cosmetic composition of embodiment 46 or 47,which comprises a compound of Formula I and a compound of Formula II, ora compound of Formula III and a compound of Formula IV.49. A method of treating a mitochondrial disease, a mitochondria-relateddisease or condition, or a disease or condition characterized by acuteNAD⁺ depletion due to DNA damage, comprising administering to a subjectin need of treatment a therapeutically effective amount of one or morecompounds of any one of the preceding embodiments or a pharmaceuticallyacceptable salt, solvate, hydrate, clathrate, polymorph or stereoisomerthereof, or a pharmaceutical composition comprising the same.50. The method of embodiment 49, wherein the mitochondrial disease isselected from mitochondrial myopathies; limb-girdle distributionweakness: Kearns-Sayre syndrome (KSS); Pearson syndrome; Leigh syndrome;Barth syndrome; Friedreich's ataxia; neuropathy, ataxia, retinitispigmentosa and ptosis (NARP); mitochondrial DNA depletion syndrome(Alper's disease); mitochondrial neurogastrointestinal encephalopathy(MNGIE) syndrome; mitochondrial encephalopathy, lactic acidosis andstroke-like episodes (MELAS) syndrome; myoclonic epilepsy with raggedred fibers (MERRF); chronic progressive external ophthalmoplegia (CPEO);Leber's hereditary optic neuropathy (LION); inherited forms of blindnessand deafness (e.g., diabetes mellitus and deafness); and acquired formsof reversible or permanent hearing loss (e.g., type 2diabetes-associated hearing loss and hearing loss induced by ototoxicchemicals (e.g., heavy metals [e.g., lead], solvents [e.g. styrene andtoluene] and asphyxiants [e.g., carbon monoxide]) and medications (e.g.,loop diuretics [e.g., bumetanide and furosemide], NSAIDs [e.g., aspirin,celecoxib, diclofenac, ibuprofen and naproxen], PDE5 inhibitors,macrolide antibiotics, aminoglycosides [e.g., gentamicin],platinum-based chemotherapeutics [e.g., carboplatin and cisplatin],paracetamol and quinine)}.51. The method of embodiment 49, wherein the mitochondria-relateddisease or condition is a neurodegenerative disorder, a neuronalactivation disorder, a muscle disorder, a fatty acid/beta oxidationdisorder, a metabolic disorder, an inflammatory disorder, a vasculardisorder, a kidney disorder, a liver disorder, a tumor or cancer, maleor female infertility, or an aging-related disorder.52. The method of embodiment 49 or 51, wherein the mitochondria-relateddisease or condition is selected from lipodystrophy, metabolic syndrome,obesity, types 1 and 2 diabetes, non-alcoholic fatty liver disease(NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic liver disease,autoimmune hepatitis, cholestatic liver disease, hemochromatosis andalpha-1 antitrypsin deficiency.53. The method of embodiment 49, wherein the disease or conditioncharacterized by acute NAD⁺ depletion due to DNA damage is selected fromexposure to radiation (e.g., UV and ionizing radiation such as X-ray),radiation or chemotherapy-induced disorders (e.g., dermatitis, myositis,myocarditis, colitis, prostatitis, hepatitis, pneumonitis, neuropathiesand bone marrow failure), burn injuries (including first-degree burns,second-degree burns and third-degree burns), chemical exposure withmanifestation of exfoliative dermatitis, exposure to chemical warfareagents, Stevens-Johnson syndrome, acute respiratory distress syndrome,inhalational lung injury due to smoke or chemical toxins, trauma-relatedcrush injuries (including those with bone fractures), peripheral nerveinjuries, spinal cord injuries, and contusion to internal organs (suchas the heart, lung, liver, and kidneys).54. The method of any one of embodiments 49 to 53, wherein the one ormore compounds are or comprise a compound of Formula II or IV.55. The method of any one of embodiments 49 to 54, wherein the one ormore compounds are or comprise a compound of Formula I and a compound ofFormula II, or a compound of Formula III and a compound of Formula IV.56. The method of any one of embodiments 49 to 55, wherein the one ormore compounds or the pharmaceutical composition is/are administeredorally, parenterally (e.g., intravenously, intradermally,subcutaneously, intramuscularly or intrathecally), or topically (e.g.,transdermally, transmucosally, intranasally, pulmonarily [e.g., by oralinhalation], sublingually or rectally [e.g., by suppository]).57. The method of any one of embodiments 49 to 55, wherein the one ormore compounds or the pharmaceutical composition is/are used in culturemedium for preparation of ex vivo therapy.58. The method of embodiment 57, wherein the ex vivo therapy is achimeric antigen receptor T-cell (CAR-T) therapy, a stem cell therapy,in vitro fertilization, organ transplantation or for attachment to acarrier molecule such as a dendrimer or an antibody conjugate.59. The method of any one of embodiments 49 to 58, further comprisingadministering a therapeutically effective amount of at least one othertherapeutic agent selected from sirtuin-activating agents,AMPK-activating agents, CD38 inhibitors, PARP inhibitors, stimulators ofcellular oxygen consumption, NMDA receptor antagonists,acetylcholinesterase inhibitors, antidiabetics, anti-obesity agents,antiplatelet agents, anticoagulants, antihypertensive agents,antioxidants, anti-inflammatory agents, analgesics, anesthetics,anticancer agents, antivirals, antibiotics, antifungals, naturalcompounds, vitamins, vaccines, and combinations thereof.60. The method of embodiment 59, wherein the at least one othertherapeutic agent is or comprises a sirtuin-activating agent, a PARPinhibitor, an antioxidant, a natural compound or a vitamin, or anycombination thereof.61. The method of embodiment 59 or 60, wherein the sirtuin-activatingagent is selected from polyphenols (e.g., butein, fisetin,isoliquiritigenin, piceatannol, quercetin and resveratrol), amino acidswith a branched side chain (e.g., leucine), methylene blue, SRT-1460,SRT-1720, SRT-2104, SRT-2183 and lamin A.62. The method of embodiment 59 or 60, wherein the PARP inhibitor isselected from niraparib, olaparib, pamiparib (BGB290), rucaparib,talazoparib, veliparib, 4-amino-1,8-naphthalimide, CEP9722, E7016 andPJ34.63. The method of embodiment 62, wherein the PARP inhibitor (e.g.,olaparib) is administered in a dose significantly lower than itsrecommended dose as an anticancer agent.64. The method of embodiment 59 or 60, wherein the antioxidant or/andthe natural compound is/are selected from resveratrol, pterostilbene,ellagic acid, urolithin A, quercetin, coenzyme Q, glutathione,N-acetyl-L-cysteine, α-lipoic acid, melatonin, creatine, S-adenosylmethionine, leucine, pyruvic acid/pyruvate, and combinations thereof.65. The method of embodiment 59 or 60, wherein the vitamin is a memberof the vitamin B family selected from thiamine (B₁), riboflavin (B₂),niacin (B₃), pantothenic acid (B₅), pyridoxine (B₆), biotin (B₇), folicacid (B₉), cobalamin (B₁₂), and combinations thereof, such as B₁, B₂, B₃or B₆ or any combination thereof.66. The method of embodiment 59, wherein the anti-inflammatory agent isselected from NSAIDs, inhibitors of pro-inflammatory cytokines andreceptors therefor and their production, and combinations thereof.67. The method of embodiment 59, wherein the antidiabetic agent isselected from AMPK agonists (e.g., metformin), PPAR-γ agonists, GLP-1agonists, SGLT2 inhibitors, and combinations thereof.68. The method of embodiment 59, wherein the antibiotic comprisesethionamide and optionally SMARt-420.69. The method of embodiment 59, wherein the anticancer agent comprisesradiation therapy, chemotherapy or cancer immunotherapy, or anycombination or all thereof.70. The method of embodiment 69, wherein the chemotherapy comprises aPARP inhibitor (e.g., olaparib), a TGF-β, inhibitor or a cytotoxicagent, or any combination or all thereof.71. The method of embodiment 69, wherein the cancer immunotherapycomprises an anti-PD1 agent, an anti-PDL1 agent or an anti-CTLA4 agent,or any combination thereof.72. One or more compounds of any one of embodiments 1 to 45 or apharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorphor stereoisomer thereof for use as a medicament.73. A composition comprising one or more compounds of any one ofembodiments 1 to 45 or a pharmaceutically acceptable salt, solvate,hydrate, clathrate, polymorph or stereoisomer thereof for use as amedicament.74. Use of one or more compounds of any one of embodiments 1 to 45 or apharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorphor stereoisomer thereof in the preparation of a medicament.75. The compound(s), the composition or the use of embodiment 72, 73 or74, respectively, wherein the one or more compounds are or comprise acompound of Formula II or IV.76. The compound(s), the composition or the use of embodiment 72, 73 or74, respectively, wherein the one or more compounds are or comprise acompound of Formula I and a compound of Formula II, or a compound ofFormula III and a compound of Formula IV.77. The compound(s), the composition or the use of embodiment 72, 73 or74, respectively, or embodiment 75 or 76, wherein the medicament is foruse in treating a mitochondrial disease, a mitochondria-related diseaseor condition, or a disease or condition characterized by acute NAD⁺depletion due to DNA damage.78. The compound(s), the composition or the use of embodiment 77, whichis in combination with the use of at least one other therapeutic agent.79. A method of elevating nicotinamide adenine dinucleotide (NAD⁺) levelor/and providing cytoprotection in at least one cell type, tissue ororgan of a subject, comprising administering to the subject atherapeutically effective amount of, or contacting the at least one celltype, tissue or organ of the subject with, one or more compounds of anyone of embodiments 1 to 45 or a pharmaceutically acceptable salt,solvate, hydrate, clathrate, polymorph or stereoisomer thereof, or apharmaceutical composition comprising the same.80. The method of embodiment 79, wherein the subject suffers from adisorder or condition characterized by NAD⁺ depletion or/and cellinjury, damage or death.81. The method of embodiment 80, wherein the NAD⁺ depletion or/and thecell injury, damage or death are associated with or result from DNAdamage.82. The method of any one of embodiments 79 to 81, wherein the one ormore compounds elevate NAD⁺ level in the mitochondria, the cytoplasmor/and the nucleus of a cell (e.g., total cellular NAD⁺ level).83. The method of any one of embodiments 79 to 82, wherein the providingcytoprotection comprises reducing cell injury, damage or death.84. The method of any one of embodiments 79 to 83, wherein the one ormore compounds are or comprise a compound of Formula II or IV.85. The method of any one of embodiments 79 to 84, wherein the one ormore compounds are or comprise a compound of Formula I and a compound ofFormula II, or a compound of Formula III and a compound of Formula IV.86. A method of increasing nicotinamide adenine dinucleotide (NAD⁺)level or/and providing cytoprotection in at least one cell type, tissueor organ of a subject, or treating a mitochondrial disease, amitochondria-related disease or condition, or a disease or condition ofa subject characterized by acute NAD⁺ depletion due to DNA damage,comprising administering to the subject a therapeutically effectiveamount of one or more nicotinyl riboside compounds and a therapeuticallyeffective amount of a poly(ADP-ribose) polymerase (PARP) inhibitor, orcontacting the at least one cell type, tissue or organ of the subjectwith one or more nicotinyl riboside compounds and a PARP inhibitor.87. The method of embodiment 86, wherein the subject suffers from adisorder or condition characterized by NAD⁺ depletion or/and cellinjury, damage or death.88. The method of embodiment 87, wherein the NAD⁺ depletion or/and thecell injury, damage or death are associated with or result from DNAdamage.89. The method of any one of embodiments 86 to 88, wherein theincreasing NAD⁺ level comprises increasing NAD⁺ level in themitochondria, the cytoplasm or/and the nucleus of a cell (e.g., totalcellular NAD⁺ level).90. The method of embodiment 89, wherein the one or more nicotinylriboside compounds and the PARP inhibitor increase NAD⁺ level (e.g.,total cellular NAD⁺ level, such as that in target cells) by at leastabout 50%, 100% (2-fold), 3-fold or 5-fold ex vivo or in vivo.91. The method of any one of embodiments 86 to 90, wherein the providingcytoprotection comprises reducing cell injury, damage or death.92. The method of embodiment 91, wherein the one or more nicotinylriboside compounds and the PARP inhibitor increase the number of viablecells (e.g., target cells) by at least about 20%, 50%, 100% or 200% exvivo or in vivo.93. The method of any one of embodiments 86 to 92, wherein the one ormore nicotinyl riboside compounds are or comprise one or more ofnicotinamide riboside (NR), reduced NR (NRH), nicotinic acid riboside(NAR), reduced NAR (NARH) and pharmaceutically acceptable salts andstereoisomers thereof, or/and one or more derivatives thereof (NR/NARderivatives).94. The method of embodiment 93, wherein the one or more nicotinylriboside compounds are or comprise NR or/and NRH, or a pharmaceuticallyacceptable salt, solvate, hydrate, clathrate, polymorph or stereoisomerthereof.95. The method of embodiment 93 or 94, wherein the one or more NR/NARderivatives are or comprise nicotinamide riboside triacetate (NRTA)or/and reduced NRTA (NRHTA), or a pharmaceutically acceptable salt,solvate, hydrate, clathrate, polymorph or stereoisomer thereof.96. The method of any one of embodiments 93 to 95, wherein the one ormore NR/NAR derivatives are or comprise one or more compounds of any oneof embodiments 1 to 45 or a pharmaceutically acceptable salt, solvate,hydrate, clathrate, polymorph or stereoisomer thereof.97. The method of embodiment 96, wherein the one or more NR/NARderivatives are or comprise a compound of Formula II or IV.98. The method of embodiment 96 or 97, wherein the one or more NR/NARderivatives are or comprise a compound of Formula I and a compound ofFormula II, or a compound of Formula III and a compound of Formula IV.99. The method of any one of embodiments 86 to 98, wherein thetherapeutically effective amount of each of the one or more nicotinylriboside compounds independently is from about 1, 50 or 100 mg to about500 or 1000 mg per day, or is about 1-100 mg, 100-200 mg, 200-300 mg,300-400 mg, 400-500 mg or 500-1000 mg per day.100. The method of any one of embodiments 86 to 99, wherein the PARPinhibitor is selected from niraparib, olaparib, pamiparib (BGB290),rucaparib, talazoparib, veliparib, 4-amino-1,8-naphthalimide, CEP9722,E7016, PJ34, and pharmaceutically acceptable salts thereof.101. The method of any one of embodiments 86 to 100, wherein thetherapeutically effective amount of the PARP inhibitor is significantlylower than its recommended dose as an anticancer agent.102. The method of embodiment 101, wherein the therapeutically effectiveamount of the PARP inhibitor is no more than about 10%, 5%, 1%, 0.5% or0.1% (e.g., no more than about 1%) of its recommended dose as ananticancer agent.103. The method of any one of embodiments 86 to 102, wherein the PARPinhibitor is olaparib, and the therapeutically effective amount (e.g.,per day or per dose) of olaparib is no more than about 10 mg, 5 mg, 1mg, 0.5 mg or 0.1 mg (e.g., no more than about 1 mg); or is from about0.01 or 0.1 mg to about 10 mg, from about 0.01 or 0.1 mg to about 1 mg,or from about 1 mg to about 10 mg; or is about 0.01-0.1 mg, 0.1-0.5 mg,0.5-1 mg, 1-5 mg or 5-10 mg; or is about 10 μg, 50 μg, 0.1 mg, 0.5 mg, 1mg, 5 mg or 10 mg.104. The method of any one of embodiments 86 to 103, wherein the one ormore nicotinyl riboside compounds and the PARP inhibitor synergisticallyincrease NAD⁺ level or/and provide cytoprotection (e.g., reducecytotoxicity), or have a synergistic therapeutic effect.105. A kit comprising a pharmaceutical or cosmetic compositioncomprising one or more compounds of any one of embodiments 1 to 45, orone or more nicotinyl riboside compounds and a PARP inhibitor, and oneor more pharmaceutically acceptable carriers or excipients.106. The kit of embodiment 105, wherein the one or more compounds, orthe one or more nicotinyl riboside compounds, are or comprise:

-   -   1) a compound of Formula II or IV; or    -   2) a compound of Formula I and a compound of Formula II; or    -   3) a compound of Formula III and a compound of Formula IV.        107. The kit of embodiment 105 or 106, wherein the one or more        nicotinyl riboside compounds are or comprise NR or/and NRH, or a        pharmaceutically acceptable salt, solvate, hydrate, clathrate,        polymorph or stereoisomer thereof.        108. The kit of any one of embodiments 105 to 107, wherein the        one or more nicotinyl riboside compounds are or comprise NRTA        or/and NRHTA, or a pharmaceutically acceptable salt, solvate,        hydrate, clathrate, polymorph or stereoisomer thereof.        109. The kit of any one of embodiments 105 to 108, wherein the        amount of the PARP inhibitor in the pharmaceutical or cosmetic        composition is significantly lower than its recommended dose as        an anticancer agent.        110. The kit of any one of embodiments 105 to 109, wherein the        PARP inhibitor is olaparib.        111. The kit of any one of embodiments 105 to 110, wherein the        pharmaceutical or cosmetic composition is a controlled-release,        slow-release or sustained-release form.        112. The kit of any one of embodiments 105 to 111, wherein the        pharmaceutical or cosmetic composition is an oral dosage form,        such as a tablet, capsule or pill.        113. The kit of any one of embodiments 105 to 112, further        comprising instructions for using or administering the        pharmaceutical or cosmetic composition to treat a mitochondrial        disease, a mitochondria-related disease or condition, a disease        or condition characterized by acute NAD⁺ depletion due to DNA        damage, or a skin disorder or condition.        114. The kit of embodiment 113, wherein the mitochondria-related        disease or condition is a metabolic disorder.

Synthesis of NR and NAR Derivatives Abbreviations

-   ACN=acetonitrile-   DCC=N,N′-dicyclohexylcarbodiimide-   DMAP=4-dimethylaminopyridine-   DMF=N,N-dimethylformamide-   DMP or 2,2-DMP=2,2-dimethoxypropane-   HMDS=hexamethyldisilazide-   MeOH=methanol-   —OAc=acetate-   p-TSA=para-toluenesulfonic acid-   Py.=pyridine-   tBuMgCl=tert-butylmagnesium chloride-   TBSCl=tert-butyldimethylsilyl chloride-   TEA=triethylamine-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran-   TLC=thin-layer chromatography-   TMSOTf=trimethylsilyl trifluromethanesulfonate

Compounds of Formulas I and II can be synthesized using the exemplaryprocess shown in FIG. 1 . The process in FIG. 1 can be adapted toprepare compounds of Formulas III and IV.

Compounds MP-05, MP-06, MP-07 and MP-08 are synthesized starting fromperacetylated β-D-ribofuranose. Standard Vorbrüggen's conditions areemployed to obtain common intermediates 3 and 4. Functional groupmanipulations of intermediate 4 using reported protocols for therespective target compounds result in the synthesis of MP-05, MP-06,MP-07 and MP-08.

Compounds MP-09 and MP-10 are synthesized from intermediate 3 withesterification of the required functional groups toward the end of thesynthesis. Compounds MP-12 through MP-24 are synthesized fromintermediate 4, with reduction of the nicotinamide ring followed byfunctional group modifications as shown in FIG. 1 , and subsequentregeneration of the aromatic nicotinamide ring.

Synthesis of MP-05 and MP-06:

FIG. 2 shows an exemplary process for synthesizing compounds MP-05 andMP-06. Their synthesis starts from commercially available peracetylatedβ-D-ribofuranose 1, the first step being the glycosylation of 1 withnicotinamide using Vorbrüggen's protocol. Selective protection of5′-hydroxyl with TBSCl followed by bis-acylation using propanoylchloride (or propionic anhydride) yields advanced intermediate 5.Deprotection of 5′-OTBS yields MP-05, and reduction of the nicotinamidering with sodium dithionite generates MP-06.

Synthesis of MP-07 and MP-08:

FIG. 3 shows an exemplary process for synthesizing NAR derivatives MP-07and MP-08, which is similar to the process for synthesizing NRderivatives MP-05 and MP-06 in FIG. 2 , except that nicotinic acid isused in lieu of nicotinamide in the Vorbrüggen glycosylation reaction.

Synthesis of MP-09 and MP-10:

FIG. 4 shows an exemplary process for synthesizing compounds MP-09 andMP-10. NARH 1 in FIG. 4 is prepared by sodium dithionite reduction ofintermediate 3 in FIG. 3 . DCC-mediated coupling of NARH 1 withL-cartinine furnishes MP-10, whose oxidation by cobalt acetate yieldsMP-09. It is understood that both L-cartinine itself and the L-cartininemoiety of MP-09 and MP-10 can be a zwitterion.

Synthesis of MP-14 and MP-16:

FIG. 5 shows an exemplary process for synthesizing compounds MP-14 andMP-16. NRH (MP-04) is prepared by sodium dithionite reduction of NR 3 inFIG. 2 . After oxidation and deprotection of the dimethyl ketal group of5′-phosphoramidate intermediate 3, bis-acylation of the resulting MP-11generates MP-14. Similarly, deprotection of intermediate 3 withoutoxidation and bis-acylation of the resulting MP-13 generate MP-16.

Synthesis of MP-12 and MP-15 and their Reduced Forms:

FIG. 6 shows an exemplary process for synthesizing compounds MP-12 andMP-15. Oxidation and deprotection of the dimethyl ketal group of5′-phosphoramidate intermediate 3 afford MP-12, whose bis-acylationproduces MP-15. Deprotection of the dimethyl ketal group of intermediate3 yields the reduced form of MP-12, and bis-propanoylation of thereduced form of MP-12 generates the reduced form of MP-15.

Synthesis of MP-17, MP-20, MP-23 and MP-24:

FIG. 7 shows an exemplary process for synthesizing MP-17, MP-20, MP-23and MP-24. Reduction of intermediate 4 with sodium dithionite followedby coupling with the indicated phosphorodiamidate reagent affords commonintermediate 5. Oxidation and deprotection of the dimethyl ketal groupof intermediate 5 produce MP-17, whose bis-acylation yields MP-20.Similarly, deprotection of intermediate 5 without oxidation furnishesMP-23, whose bis-acylation yields MP-24.

Synthesis of MP-18, MP-19, MP-21 and MP-22:

FIG. 8 shows an exemplary process for synthesizing MP-18, MP-19, MP-21and MP-22. Intermediate 5 in FIG. 8 is prepared in a similar manner asintermediate 5 in FIG. 7 except that ethylnicotinate is used instead ofnicotinamide in the Vorbrüggen glycosylation reaction. Deprotection ofthe dimethyl ketal group of intermediate 5 furnishes MP-19.Bis-acylation of MP-19 yields MP-22, while oxidation of MP-19 yieldsMP-18. MP-21 can be made by bis-acylation of MP-18 or oxidation ofMP-22.

EXAMPLES

The following examples are intended only to illustrate the disclosure.Other processes, assays, studies, protocols, procedures, methodologies,reagents and conditions may alternatively be used as appropriate.

Example 1. Synthesis of1-((2R,3R,4S,5R)-5-(((Bis(((S)-1-methoxy-1-oxopropan-2-yl)amino)phosphoryl)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)-3-carboxamidepyridin-1-iumtrifluoroacetate (MP-17) and1-((2R,3R,4R,5R)-5-(((bis(((S)-1-methoxy-1-oxopropan-2-yl)amino)phosphoryl)oxy)methyl)-3,4-bis(propionyloxy)tetrahydrofuran-2-yl)-3-carboxamidepyridin-1-iumtrifluoroacetate (MP-20)

FIG. 9 shows the process for the synthesis of MP-17 and MP-20.

3-Carboxamide-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)pyridiniumtriflate (2)

To a well stirred solution of nicotinamide (115.2 g, 0.942 mol) in dryacetonitrile (1.5 L) was added trimethylsilyl trifluoromethanesulfonate(314 mL, 1.72 mol) in one portion. The nicotinamide was dissolved within5 min. A solution of 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose 1 (100 g,0.314 mol) in dry acetonitrile (300 mL) was added all in one portion atroom temperature under nitrogen atmosphere. The solution was stirred for30 min at room temperature. The excess TMSOTf was quenched by theaddition of 1.2 M NaHCO₃ solution (10 mL) followed by solid NaHCO₃ (85g, 1.01 mol) in small portions. The suspension was stirred for 30 min atroom temperature and the solids were filtered and washed with CH₂Cl₂(500 mL). Combined filtrates were concentrated under reduced pressure toget a thick yellow residue. The residue was suspended in 2 L of CH₂Cl₂.The suspension was stirred at room temperature for 15 min, and thensolids were filtered and washed with CH₂Cl₂ (2 L). The filtrate wasconcentrated under vacuum to obtain compound 2 (120 g crude of which 82%was product by LCMS) as a yellow syrup. ¹H NMR (400 MHz, DMSO-d₆): δ9.46 (s, 1H), 9.24 (d, J=6.24 Hz, 1H), 9.06 (d, J=8.1 Hz, 1H), 8.67 (s,1H), 8.40 (t, J=6.5 Hz, 1H), 8.25 (s, 1H), 6.65 (d, J=3.3 Hz, 1H),5.61-5.62 (m, 1H), 5.44 (t, J=5.92 Hz, 1H), 4.70-4.71 (m, 1H), 4.45 (s,2H), 2.15 (s, 3H) and 2.11 (s, 3H). LCMS (M⁺): 381.1.

3-Carboxamide-1-(β-D-ribofuranosyl)pyridinium triflate (3)

To a well-stirred solution of crude compound 2 (120 g) in anhydrous MeOH(1.5 L) was added 1N NaOMe/MeOH (750 mL, 0.75 mol) dropwise over 10 min.The internal temperature was maintained below 5° C. and the reactionmixture was stirred at 0° C. for 0.5 hr, and the progress of thereaction was monitored by LCMS. Then 250 mL of 3 M HCl was added slowly,keeping the internal temperature below 5° C. Excess solvent was removedunder reduced pressure below 20° C. to afford crude compound 3 (80 g,78% pure by LCMS). ¹H NMR (400 MHz, D₂O): δ 9.49 (s, 1H), 9.16 (d, J=5.9Hz, 1H), 8.88 (t, J=7.2 Hz, 1H), 8.57 (d, J=3.8 Hz, 1H), 6.15 (s, 1H),4.37-4.38 (m, 2H), 4.25 (t, J=4.7 Hz, 1H), 3.95 (d, J=12.9 Hz, 1H) and3.78-3.81 (m, 1H). LCMS (M⁺): 255.1.

3-Carboxamide-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)pyridiniumtriflate (4)

Into a 50 mL double-neck round-bottom flask containing concentratedsulfuric acid (160 mg, 1.62 mmol) was added dry acetonitrile (8 mL) at0° C. under inert atmosphere. After stirring for 5 minutes,2,2-dimethoxypropane (2.5 mL) and a solution of compound 3 (1 g, 2.475mmol) in dry acetonitrile (2 mL) already cooled at 0° C. were added tothe flask, and the resulting reaction mixture was stirred at 0° C. for30 minutes. After completion of the reaction (monitored by TLC), excessacid was quenched with solid sodium carbonate (202 mg, 0.77 mmol) in thepresence of water (0.2 mL) at 0° C. with stirring for 30 minutes, andthen the reaction mixture was passed through a pad of Celite and theCelite bed was washed with acetonitrile (2×10 mL). Combined filtrateswere concentrated under reduced pressure to afford a crude mass.Purification of the crude mass by silica-gel column chromatography withMeOH/CH₂Cl₂ (0-10%) yielded compound 4 (400 mg, 34%) as a waxy off-whitesolid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.43 (s, 1H), 9.30 (d, J=6 Hz, 1H),9.00 (t, J=7.9 Hz, 1H), 8.65 (s, 1H), 8.29 (t, J=7.8 Hz, 1H), 8.21 (s,1H), 6.47 (s, 1H), 5.24-5.25 (m, 2H), 4.92 (d, J=5.7 Hz, 1H), 4.74 (s,1H), 3.74-3.76 (m, 1H), 3.64-3.66 (m, 1H), 1.59 (s, 3H) and 1.36 (s,3H). LCMS (M⁺): 295.1.

1-((3aR,4R,6R,6aR)-6-(((Bis(((S)-1-methoxy-1-oxopropan-2-yl)amino)phosphoryl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-3-carboxamidepyridin-1-iumammonium acetate (5)

Method A Using Tert-Butyl Magnesium Chloride and p-NitrophenylBis(Methyl L-Alaninyl)Phosphate:

To a well stirred solution of compound 4 (520 mg, 1.7 mmol) in dry THE(10 mL) was added tert-butyl magnesium chloride (7 mL, 7 mmol, 1 M inTHF) under nitrogen atmosphere, and the resulting solution was stirredat room temperature for 10 minutes. To the reaction mixture was addedp-nitrophenyl bis(methyl L-alaninyl)phosphate (1 g, 2.6 mmol, preparedusing standard literature procedure) in dry THE (5 mL), and the reactionmixture was stirred at ambient temperature for 2 hr. Excess reagent wasthen quenched with MeOH (5 mL) and saturated ammonium chloride solution(2 mL). The reaction mixture was concentrated under reduced pressure toget a crude residue. The crude residue was purified by reverse-phaseprep HPLC (eluting with 10 mM ammonium acetate in acetonitrile assolvent A and water as solvent B), and column fractions containingcompound 5 furnished compound 5 (15 mg, 1.5%) as a colorless gum uponlyophilisation. LCMS (M⁺): 545.2.

Method B Using Phosphorus Oxychloride and Methyl L-Alaninate:

Into a 100 mL single-neck round-bottom flask containing a solution ofcompound 4 (2 g, 4.9 mmol) in anhydrous triethyl phosphate (TEP, 20 mL)was added phosphoryl chloride (1.67 mL, 18 mmol) at 0° C. under nitrogenatmosphere, and the resulting reaction mixture was stirred at 0° C. for48 hr. The reaction mixture was cooled to −78° C., and methylL-alaninate hydrochloride salt (3.14 g, 22 mmol) in anhydrous CH₂Cl₂ (20mL) was added to the flask. Triethylamine (6.27 mL, 45 mmol) was addedat −78° C. The reaction mixture was allowed to attain ambienttemperature with stirring, and stirring continued at ambient temperaturefor 1 hr. Excess reagent was quenched with saturated sodium carbonate(10 mL), ammonium chloride (10 mL) and water (10 mL). Dichloromethanewas removed under reduced pressure. The aqueous layer was washed with50% diethyl ether/hexane (200 mL) to remove the excess triethylphosphate, and then the aqueous layer was concentrated under reducedpressure. The residue was treated with 30% MeOH/CH₂Cl₂ (200 mL), theresulting suspension was filtered through a pad of Celite, and thefiltrate was concentrated under reduced pressure to obtain a crude mass.Purification of the crude mass by reverse-phase prep HPLC with 10 mMammonium acetate in water as solvent A and acetonitrile as solvent B andlyophilisation of the desired column fractions furnished compound 5 (200mg, 6%) as a white solid. LCMS (M+): 545.2.

1-((2R,3R,4S,5R)-5-(((Bis(((S)-1-methoxy-1-oxopropan-2-yl)amino)phosphoryl)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)-3-carboxamidepyridin-1-iumtrifluoroacetate (MP-17)

The isopropylidene 5 (10 mg) was treated with 80% aqueoustrifluoroacetic acid (2 mL) at 0° C. for 0.5 hr, and then the reactionmixture was concentrated under reduced pressure to get a crude residue.The crude residue was purified by reverse-phase prep HPLC with 0.1%trifluoroacetic acid in water as solvent A and acetonitrile as solventB, and lyophilisation of the desired column fractions yielded MP-17 (4.5mg, 48%) as a white solid. ¹H NMR (400 MHz, D₂O): δ 9.38 (s, 1H), 9.13(d, J=6.3 Hz, 1H), 8.92 (d, J=7.4 Hz, 1H), 8.21 (d, J=7.1 Hz, 1H), 6.16(s, 1H), 4.29-4.35 (m, 3H), 4.19 (s, 1H), 4.06-4.07 (m, 1H), 3.73-3.84(m, 2H), 3.60 (d, J=7.6 Hz, 6H) and 1.20 (d, J=8 Hz, 6H). LCMS (M⁺):505.1.

1-((2R,3R,4R,5R)-5-(((Bis(((S)-1-methoxy-1-oxopropan-2-yl)amino)phosphoryl)oxy)methyl)-3,4-bis(propionyloxy)tetrahydrofuran-2-yl)-3-carboxamidepyridin-1-iumtrifluoroacetate (MP-20)

Into a 50 mL single-neck round-bottom flask containing MP-17 (40 mg) ina mixture of anhydrous pyridine (2 mL) and acetonitrile (10 mL) wasadded propanoic anhydride (0.4 mL) at ambient temperature under nitrogenatmosphere, and the reaction mixture was stirred at ambient temperaturefor 16 hr. The reaction mixture was concentrated under reduced pressure,and the crude mass was purified by reverse-phase prep HPLC with 0.1%trifluoroacetic acid in water as solvent A and acetonitrile as solventB. Lyophilisation of the desired column fractions furnished MP-20 (12mg, 50%) as a white solid. ¹H NMR (400 MHz, D₂O): δ 9.43 (s, 1H), 9.16(d, J=6.2 Hz, 1H), 8.97 (d, J=8 Hz, 1H), 8.25 (t, J=6.5 Hz, 1H), 6.54(d, J=4.7 Hz, 1H), 5.43-5.44 (m, 2H), 4.82 (s, 1H), 4.40 (t, J=1.5 Hz,1H), 4.25-4.25 (m, 1H), 3.87 (t, J=7.4 Hz, 2H), 3.61 (d, J=19.5 Hz, 6H),2.39-2.41 (m, 4H), 1.28 (d, J=7.04 Hz, 6H) and 1.00-1.02 (m, 6H). LCMS(M⁺): 617.3.

Example 2. Synthesis of1-((2R,3R,4S,5R)-5-(((L-Valyl)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)-3-carboxamidepyridin-1-iumtrifluoroacetate (MP-41)

FIG. 10 shows the process for the synthesis of MP-41.

1-((3aR,4R,6R,6aR)-6-((((tert-Butoxycarbonyl)-L-valyl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-3-carboxamidepyridin-1-iumtriflate (8)

To a well stirred solution of compound 4 (700 mg, 1.6 mmol, preparedaccording to Example 1) in anhydrous THE (10 mL) were added(tert-butoxycarbonyl)-L-valine (618.4 mg, 2.84 mmol) andtriphenylphosphine (TPP, 932.9 mg, 3.558 mmol) at ambient temperatureunder nitrogen atmosphere. The reaction mixture was stirred for 5 min atambient temperature, and then diisopropyl azodicarboxylate (DIAD, 719.4mg, 3.558 mmol) was added. The reaction mixture was stirred for 16 hr atroom temperature. After completion of the reaction (monitored by LCMS),the reaction mixture was concentrated under reduced pressure to getcrude compound 8 (3 g) as a thick viscous orange liquid, which was usedin the next step without further purification. LCMS (M⁺): 494.

1-((2R,3R,4S,5R)-5-(((L-Valyl)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)-3-carboxamidepyridin-1-iumtrifluoroacetate (MP-41)

To a well stirred solution of compound 8 (750 mg, 1.518 mmol) inanhydrous CH₂Cl₂ (20 mL) was added 2 mL of trifluoroacetic acid underinert atmosphere at 0° C., and the reaction mixture was stirred atambient temperature for 1 hr. After completion of the reaction(monitored by LCMS), the reaction mixture was concentrated under reducedpressure. The crude residue was purified by reverse-phase HPLC to affordMP-41 (150 mg) as an off-white solid. ¹H NMR (400 MHz, CD₃OD): δ9.52 (s,1H), 9.20 (d, J=6.2 Hz, 1H), 9.09 (d, J=8.1 Hz, 1H), 8.31-8.34 (m, 1H),6.25 (d, J=4.1 Hz, 1H), 4.75 (t, J=14 Hz, 1H), 4.63-4.68 (m, 2H), 4.39(t, J=9 Hz, 1H), 4.27-4.32 (m, 2H), 2.29-3.37 (m, 1H) and 1.08-1.11 (m,6H). LCMS (M⁺): 354.

Example 3. Synthesis of3-Carboxamide-1-((2R,3R,4S,5R)-5-(((3-carboxypropanoyl)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-iumtrifluoroacetate (MP-42)3-Carboxamide-1-((3aR,4R,6R,6aR)-6-(((3-carboxypropanoyl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)pyridin-1-iumformate (10)

Into a 100 mL single-neck round-bottom flask containing a well stirredsolution of compound 4 (1 g, 2.25 mmol, prepared according to Example 1)in a mixture of anhydrous pyridine (15 mL) and CH₂Cl₂ (5 mL) was addedsuccinic anhydride (3.37 g, 33.7 mmol) at ambient temperature undernitrogen atmosphere. The reaction mixture was stirred at roomtemperature overnight, and then was concentrated under reduced pressure.The crude mass was purified by reverse-phase HPLC with 0.1% formic acidin water as solvent A and acetonitrile as solvent B to yield compound 10(500 mg, 41%) as a colorless syrupy liquid. ¹H NMR (400 MHz, D₂O): δ9.33 (s, 1H), 9.14 (d, J=6.4 Hz, 1H), 8.94 (d, J=8 Hz, 1H), 8.25-8.21(m, 1H), 6.43 (d, J=2 Hz, 1H), 5.26 (t, J=2.4 Hz, 1H), 4.99 (d, J=6 Hz,2H), 4.41 (s, 2H), 3.61 (s, 4H), 2.46-2.42 (m, 2H), 2.32-2.26 (m, 1H),2.10-2.03 (m, 1H), 1.59 (s, 3H) and 1.38 (s, 3H). LCMS (M⁺): 395.1.

3-Carboxamide-1-((2R,3R,4S,5R)-5-(((3-carboxypropanoyl)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyridin-1-iumtrifluoroacetate (MP-42)

Into a 25 mL single-neck round-bottom flask containing a well stirredsolution of compound 10 (100 mg, 0.18 mmol) in CH₂Cl₂ (5 mL) was added80% aqueous trifluoroacetic acid (5 mL) at 0° C. The reaction mixturewas stirred at ambient temperature for 2 hr, and then was concentratedunder reduced pressure. The crude product was purified by reverse-phaseHPLC with 0.1% trifluoroacetic acid in water as solvent A andacetonitrile as solvent B to afford MP-42 (20 mg, 23%) as a colorlesssyrup. ¹H NMR (400 MHz, D₂O): δ 9.53 (s, 1H), 9.26 (d, J=6.4 Hz, 1H),9.08-9.05 (m, 1H), 8.34-8.31 (m, 1H), 6.20 (d, J=5.2 Hz, 1H), 4.63-4.61(m, 1H), 4.53 (t, J=3.6 Hz, 2H), 4.37 (t, J=5.2 Hz, 1H), 4.29-4.27 (m,1H) and 2.63 (s, 4H). LCMS (M⁺): 355.1.

Example 4. Synthesis of3-Carboxamide-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(((4-methoxy-4-oxobutanoyl)oxy)methyl)tetrahydrofuran-2-yl)pyridin-1-iumtrifluoroacetate (MP-43)

3-Carboxamide-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(((4-methoxy-4-oxobutanoyl)oxy)methyl)tetrahydrofuran-2-yl)pyridin-1-iumtrifluoroacetate (MP-43)

Into a 25 mL single-neck round-bottom flask containing a well stirredsolution of compound 3 (368 mg, 1 mmol, prepared according to Example 1)in anhydrous DMF (5 mL) were added 2-chloropyridine (1.76 g, 15.51 mmol)and methyl 4-chloro-4-oxobutanoate (1.09 g, 7.23 mmol) at ambienttemperature under nitrogen atmosphere. The reaction mixture was stirredat ambient temperature for 0.5 hr, the acid chloride was quenched withexcess MeOH, and the reaction mixture was concentrated under reducedpressure. The crude product was purified by reverse-phase HPLC with 0.1%trifluoroacetic acid in water as solvent A and acetonitrile as solvent Bto yield MP-43 (20 mg, 4%) as a colorless syrup. ¹HNMR (400 MHz, D₂O): δ9.54 (s, 1H), 9.26 (d, J=6 Hz, 1H), 9.08 (d, J=8 Hz, 1H), 8.35-8.32 (m,1H), 6.21 (d, J=5.2 Hz, 1H), 4.62-4.61 (m, 1H), 4.54-4.51 (m, 2H),4.38-4.36 (m, 1H), 4.28-4.26 (m, 1H), 3.65 (s, 3H) and 2.66 (s, 4H).LCMS (M⁺): 369.1.

Example 5. Elevation of NAD⁺ Level and Reduction of Cytotoxicity afterAcute NAD⁺ Depletion and Cytotoxicity Induced by DNA Damage

Test NR derivatives were evaluated for their ability to increase NAD⁺level and reduce cellular toxicity after acute NAD⁺ depletion andcytotoxicity induced by DNA damage. HEPG2 (liver), HEK (kidney) andJurkat (T-cells) cell lines were obtained from ATCC. HEPG2 and HEK cellswere incubated in Dulbecco's Modified Eagle Medium (DMEM) (ThermoFischer) with 5% fetal bovine serum (FBS), while Jurkat cells wereincubated in RPMI 1640 medium (Gibco). DNA damage in the cells wasinduced using the DNA-alkylating mutagenN-methyl-N-nitroso-N′-nitroguanidine (MNNG). Dose-response relationshipsof concentrations of MNNG and the magnitude of NAD⁺ depletion andcytotoxicity were established in the three different cell lines.Briefly, cells were incubated with varying concentrations ofMNNG-containing media for 30 min. The cells were washed, and then wereincubated with varying concentrations of a test compound for 3.5 hr. Ascontrols, different combinations of incubation of the cells with orwithout MNNG for 30 min, washing of the cells, and incubation of thecells with or without a test compound for 3.5 hr were performed. Totalcellular NAD⁺ levels were measured using the NAD/NADH Glo™ Assay(Promega). Cytotoxicity was assessed using the CellTiter-Blue® CellViability Assay (Promega). About 80,000 cells per well were utilized forthe experiments.

MP-17 Reduced MNNG-Induced NAD⁺ Depletion and Cytotoxicity in JurkatCells:

Jurkat cells were incubated with or without 100 μM of MMNG for 30 min.The cells were washed, and then were incubated with or without MP-17(111-1000 μM) for 3.5 hr. MNNG treatment resulted in 76.9% depletion ofNAD⁺ level at 4 hr. Depending on the concentration of MP-17, MP-17induced 19.5% to 52.3% recovery of NAD⁺ level (FIG. 12 ).

Jurkat cells were incubated with or without 150 μM of MMNG for 30 min.The cells were washed, and then were incubated with or without MP-17(111-1000 μM) for 3.5 hr. MNNG treatment resulted in 63.2% cytotoxicityat 4 hr. MP-17 provided cytoprotection (i.e., reduced cytotoxicity) by6.9-9.2% (FIG. 13 ).

MP-41 Reduced MNNG-Induced NAD⁺ depletion and cytotoxicity in Jurkatcells:

Jurkat cells were incubated with or without 75 μM of MMNG for 30 min.The cells were washed, and then were incubated with or without MP-41(0.25-10 mM) for 3.5 hr. MNNG treatment resulted in 92.1% depletion ofNAD⁺ level at 4 hr. Depending on the concentration of MP-41, MP-41induced 31% to 172% recovery of NAD⁺ level (FIG. 14 ).

Jurkat cells were incubated with or without 75 μM of MMNG for 30 min.The cells were washed, and then were incubated with or without MP-41(0.25-10 mM) for 3.5 hr. MNNG treatment resulted in 87% cytotoxicity at4 hr. MP-41 provided cytoprotection (i.e., reduced cytotoxicity) by18-25% (FIG. 15 ).

MP-42 and MP-43 Reduced MNNG-Induced NAD⁺ Depletion and Cytotoxicity inHEPG2 and Jurkat Cells:

Using similar procedures as described above for the assays of MP-17 andMP-41 in Jurkat cells, MP-42 and MP-43 reduced MNNG-induced NAD⁺depletion and cytotoxicity in HEPG2 and Jurkat cells, as indicated inTables 1 and 2. The concentration of MNNG used in the cytotoxicityexperiments with HEPG2 cells (Table 2) was higher because these cellsare more resistant to cytotoxicity despite a large reduction in NAD⁺level.

TABLE 1 MNNG Conc. % NAD⁺ Repletion Cell Line (μM) MP-42 (1 mM) MP-43 (1mM) HEPG2 100 23.7 31.1 Jurkat 100 8.2 12.9

TABLE 2 MNNG Conc. % Cytoprotection Cell Line (μM) MP-42 (1 mM) MP-43 (1mM) HEPG2 600 9.9 5.7 Jurkat 100 4.5 6.3

Example 6. Synergistic NAD⁺ Repletion and Cytoprotection by Combinationof Nicotinamide Riboside and Very Low-Dose Olaparib

DNA damage was induced by MNNG in Jurkat cells, total cellular NAD+levels were measured, and cytotoxicity was assessed as described inExample 5. Briefly, Jurkat cells were incubated with or without 100 μMof MMNG for 30 min. The cells were washed, and then were incubated withor without 100 μM of nicotinamide riboside (NR) or 5 nM of olaparib, orboth NR and olaparib, for 3.5 hr. MNNG treatment resulted in 94%depletion of NAD⁺ level at 4 hr. NR (100 μM) without olaparib increasedNAD⁺ level by 43%, while olaparib (5 nM) without NR increased NAD⁺ levelby 8%. However, the combination of both NR (100 μM) and olaparib (5 nM)synergistically increased NAD⁺ level by 75% to a similar level as incells not treated with MNNG (FIG. 16 ). MP02 in FIGS. 16 and 17 is NR.

Jurkat cells were incubated with or without 200 μM of MMNG for 30 min.The cells were washed, and then were incubated with or without 100 μM ofNR or 5 nM of olaparib, or both NR and olaparib, for 3.5 hr. MNNGtreatment resulted in 78% cytotoxicity at 4 hr. NR (100 μM) withoutolaparib provided cytoprotection (i.e., reduced cytotoxicity) by 16%,while olaparib (5 nM) without NR provided no cytoprotection. However,the combination of both NR (100 μM) and olaparib (5 nM) synergisticallyenhanced cytoprotection by 58% to a cytotoxicity level of 20% relativeto cells not treated with MNNG (FIG. 17 ).

Example 7. Measurement of Mitochondrial Function in Primary Cells

Mitochondrial function in different cell types (e.g., neural cells,liver cells, kidney cells, lymphoma cells and peripheral bloodmononuclear cells) after exposure to NR/NAR derivatives of thedisclosure or NR (positive control) is measured. Mitochondrial mass ismeasured using the Mitotracker assay (ThermoFisher Scientific).Mitochondrial super oxide production is measured using the Mitosox assay(ThermoFisher Scientific) assay. Mitochondrial membrane potential ismeasured using the JC-1 Dye assay (ThermoFisher Scientific).

Example 8. In Vivo PK and Efficacy of NR and NAR Derivatives

In vivo pharmacokinetic studies and pharmacodynamic studies (e.g., NAD⁺levels in the blood and in different cell types, such as neural cells,liver cells and kidney cells) of orally and parenterally (e.g.,intravenously and subcutaneously) administered NR and NAR derivatives ofthe disclosure and NR (positive control) are performed in rats, and EC₅₀values are calculated.

Example 9. Stability of NR and NAR Derivatives

The stability of NR and NAR derivatives of the disclosure and NR (forcomparison) in different tyes of media is determined using HPLC-basedanalytical methods. Examples of such media include: 1) phosphate buffersat pH 2, 4, 6, 7, 7.4, 8 and 9; 2) Cell Culture Media (CCM); 3)Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetalbovine serum (FBS); 4) rat plasma; and 5) human plasma.

REFERENCES

The following citations are incorporated herein by reference in theirentirety:

-   1. Adams and Victor's Principles of Neurology, 10th Ed. (2014)-   2. Bieganowski, P. and Brenner, C., Discoveries of nicotinamide    riboside as a nutrient and conserved NRK genes establish a    Preiss-Handler independent route to NAD⁺ in fungi and humans, Cell,    117(4):495-502 (2004)-   3. Bonkowski, M. and Sinclair, D., Slowing ageing by design: the    rise of NAD and sirtuin-activating compounds, Nat. Rev. Mol. Cell    Biol., 17(11):679-690 (2016)-   4. Camacho-Pereira, J. et al., CD38 Dictates Age-Related NAD Decline    and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism,    Cell Metab., 23(6):1127-1139 (2016)-   5. Chini, C. et al., NAD and the aging process: Role in life, death    and everything in between, Mol. Cell Endocrinol., 455:62-74 (2017)-   6. Croteau, D. et al., NAD in DNA repair and mitochondrial    maintenance, Cell Cycle, 16(6):491-492 (2017)-   7. de Picciotto, N. et al., Nicotinamide mononucleotide    supplementation reverses vascular dysfunction and oxidative stress    with aging in mice, Aging Cell, 15(3):522-530 (2016)-   8. de Vita and Lawrence, Cancer: Principles and Practice of    Oncology, 10^(th) Ed. (2015)-   9. Fang, E. et al., NAD Replenishment Improves Lifespan and    Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA    Repair, Cell Metab., 24(4):566-581 (2016)-   10. Fang, E. and Bohr, V., NAD: The convergence of DNA repair and    mitophagy, Autophagy, 13(2):442-443 (2017)-   11. Frederick, D. et al., Loss of NAD Homeostasis Leads to    Progressive and Reversible Degeneration of Skeletal Muscle, Cell    Metab., 24(2):269-282 (2016)-   12. Imai, S. and Guarente, L., NAD⁺ and sirtuins in aging and    disease, Trends Cell Biol., 24(8):464-471 (2014)-   13. López-Otïn, C. et al., The Hallmarks of Aging, Cell,    153(6):1194-1217 (2013)-   14. Physician's Desk Reference, 70th Ed. (2016)-   15. WO 2015/186068 A1-   16. WO 2017/079195 A1-   17. Mills, K. et al., Long-Term Administration of Nicotinamide    Mononucleotide Mitigates Age-Associated Physiological Decline in    Mice, Cell Metab., 24(6):795-806 (2016)-   18. Ratajczak, J. et al., NRK1 controls nicotinamide mononucleotide    and nicotinamide riboside metabolism in mammalian cells, Nat.    Commun., 7:13103 (2016)-   19. Stein, L. and Imai, S., The dynamic regulation of NAD metabolism    in mitochondria, Trends Endocrinol. Metab., 23(9):420-428 (2012)-   20. Stunkard and Wadden, Obesity: Theory and Therapy, 2nd Ed. (1993)-   21. Trammell, S. et al., Nicotinamide riboside is uniquely and    orally bioavailable in mice and humans, Nat. Commun., 7:12948 (2016)-   22. U.S. Pat. No. 8,383,086-   23. Yang, Y. and Sauve, A., NAD⁺ metabolism: Bioenergetics,    signaling and manipulation for therapy, Biochim. Biophys. Acta,    1864(12):1787-1800 (2016)-   24. Zhang, H. et al., NAD⁺ repletion improves mitochondrial and stem    cell function and enhances life span in mice, Science,    352(6292):1436-1443 (2016)

While various embodiments of the present disclosure have been described,such embodiments are provided by way of illustration and example only.Numerous variations thereof and modifications thereto will be apparentto those skilled in the art and are encompassed by the presentdisclosure. It is understood that various alternatives to theembodiments of the disclosure can be employed in practicing thedisclosure and are encompassed by the disclosure.

What is claimed is:
 1. A method of increasing cytoprotection in a celltype or tissue at risk of DNA damage in a subject, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of a compound of Formula (V) or Formula (VI):

or pharmaceutically acceptable salts and a therapeutically effectiveamount of olaparib or pharmaceutically acceptable salts thereof,wherein: Y and Z are —OH or —NH₂; X⁻ is fluoride, chloride, bromide,iodide, nitrate, sulfate, sulfite, phosphate, bicarbonate, carbonate,thiocyanate, formate, acetate, trifluoroacetate, glycolate, lactate,gluconate, ascorbate, benzoate, oxalate, malonate, succinate, citrate,methanesulfonate, ethanesulfonate, propanesulfonate, benzenesulfonate,p-toluenesulfonate or trifluoromethanesulfonate; and the therapeuticallyeffective amount of olaparib is not more than about 10% of thetherapeutically effective amount of olaparib used in chemotherapy. 2.The method of claim 1, wherein the therapeutically effective amount ofolaparib is no more than about 5%, about 1%, about 0.5% or about 0.1% ofthe therapeutically effective amount olaparib used in chemotherapy. 3.The method of claim 1, wherein the therapeutically effective amount ofolaparib is no more than 10 mg, about 5 mg, about 1 mg, about 0.5 mg orabout 0.1 mg.
 4. The method of claim 3, wherein the therapeuticallyeffective amount of the compound is about 50 mg, about 100 mg, about 150mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500mg, about 600 mg, about 700 mg, about 900 mg or about 1000 mg.
 5. Themethod of claim 1, wherein the compound is


6. The method of claim 5, wherein the therapeutically effective amountof olaparib is no more than about 10 mg, about 5 mg, about 1 mg, about0.5 mg or about 0.1 mg.
 7. The method of claim 6, wherein thetherapeutically effective amount of the compound is about 50 mg, about100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about400 mg, about 500 mg, about 600 mg, about 700 mg, about 900 mg or about1000 mg.